Corticotropin releasing factor antagonists

ABSTRACT

A pharmaceutical composition for treatment of a disorder or condition the treatment of which can be effected or facilitated by antagonizing Corticotropin Releasing Factor (CRF). The pharmaceutical composition includes a pharmaceutically acceptable carrier and an effective amount to treat the disorder or condition of the following compound:  
                 
 
or a pharmaceutically acceptable salt thereof, wherein A, B, Z, R 3 , R 4 , and R 5  are as defined herein.

BACKGROUND OF THE INVENTION

This invention relates to pyridines, pyrimidines, purinones,pyrrolopyrimidinones and pyrrolopyridinones, processes for preparingthem, pharmaceutical compositions containing them, and methods of usingthem to treat certain central nervous system (CNS) and other disorders.

CRF antagonists are mentioned in U.S. Pat. No. 4,605,642, issued Aug.12, 1986, and U.S. Pat. No. 5,063,245, issued Nov. 5, 1991, referring topeptides and pyrazolinones, respectively. CRF antagonists are alsodescribed in U.S. Pat. No. 5,962,479, issued Oct. 5, 1999. Theimportance of CRF antagonists is set out in the literature, e.g., asdiscussed in U.S. Pat. No. 5,063,245, which is incorporated herein byreference. A recent outline of the different activities possessed by CRFantagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages425 to 473 (1991), also incorporated herein by reference. Based on theresearch described in these two and other references, CRF antagonistsare effective in the treatment of a wide range of stress-relatedillnesses, such as depression, anxiety, headache, irritable bowelsyndrome, inflammatory diseases, immune suppression, Alzheimer'sdisease, gastrointestinal diseases, anorexia nervosa, hemorrhagicstress, drug and alcohol withdrawal symptoms, drug addiction,infertility, head trauma, stroke, and stress-induced infections inhumans and animals. The use of CRF antagonists for treatment of SyndromeX has also been described in U.S. Provisional Patent Application No.60/162,340, filed Oct. 29, 1999, which is also incorporated in itsentirety herein by reference. Methods for using CRF antagonists to treatcongestive heart failure are described in U.S. Ser. No. 09/248,073,filed Feb. 10, 1999, which is also incorporated herein in its entiretyby reference.

SUMMARY OF THE INVENTION

The present invention provides compounds of the formula

-   -   and pharmaceutically acceptable salts thereof, wherein    -   the dashed lines represent optional double bonds, with the        proviso that when the dashed line in C=G represent a double        bond, then the dashed line in N(R₆)=C does not represent a        double bond; and with the proviso that when the dashed line in        N(R₆)=C represents a double bond, R₆ is absent in formula III        and the dashed line in C═G does not represent a double bond;    -   A is —CR₇or N;    -   B is —NR₁R₂, —CR₁R₂R₁₁, —C(═CR₂R₁₂)R₁₁, —NHCHR₁R₂, —OCHR₁R₂,        —SCHR₁R₂, —CHR₂OR₁, —CHR₁OR₂, —CHR₂SR₁, —C(S)R₂, —C(O)R₂,        —CHR₂NR₁R₂, —CHR₁NHR₂, —CHR₁N(CH₃)R₂, or —NR₁₂NR₁R₂;    -   when the dashed line in C═G represents a double bond, then G is        hydrogen, oxygen, sulfur, NH, or N(C₁-C₄ alkyl);    -   when the dashed line in C═G does not represent a double bond,        then C═G is —C(H)(NH₂), CH₂, —C(H)(methoxy), —C(H)(ethoxy),        —C(H)(O(C₃-C₄ alkyl)), —C(H)(halo), —C(H)(trifluoromethoxy),        —C(H)(methyl), —C(H)(ethyl), —C(H)(C₃-C₄ alkyl), —C(H)(S(C₁-C₄        alkyl)), —C(C₁-C₄ alkyl)(C₁-C₄ alkyl), cyclopropyl,        —C(H)(cyclopropyl), thiomethoxy, —C(H)(NH₂), —C(H)(NHCH₃),        —C(H)(N(CH₃)₂), or —C(H)(trifluoromethyl);    -   wherein said cyclopropyl, methoxy, ethoxy, C₃-C₄ alkyl, and        C₁-C₄ alkyl groups of C═G may optionally be substituted by one        OH, methoxy, or trifluoromethoxy, or may optionally be        substituted by from one to six fluoro atoms;    -   Y is CH or N;    -   Z is NH, O, S, —N(C₁-C₂ alkyl), —NC(O)CF₃, or —C(R₁₃R₁₄),        wherein R₁₃ and R₁₄ are each, independently, hydrogen,        trifluoromethyl or methyl, or one of R₁₃ and R₁₄ is cyano and        the other is hydrogen or methyl, or —C(R₁₃R₁₄) is a cyclopropyl        group, or Z is nitrogen or CH and forms a five or six membered        heterocyclic ring fused with R₅, which ring optionally comprises        two or three further hetero members selected independently from        oxygen, nitrogen, NR₁₂, and S(O)_(m), and optionally comprises        from one to three double bonds, and is optionally substituted        with halo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), NH₂, NHCH₃, N(CH₃)₂,        CF₃, or OCF₃, with the proviso that said ring does not contain        any —S—S—, —S—O—, —N—S—, or —O— bonds, and does not comprise        more than two oxygen or S(O)_(m) heterologous members;    -   R₁ is C(O)H, C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ alkylene)(C₃-C₈        cycloalkyl), C(O)(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),        C(O)(C₁-C₆ alkylene)(C₄-C₈ heterocycloalkyl), —C(O)(C₃-C₈        cycloalkylene)(C₄-C₈ heterocycloalkyl), C₁-C₆ alkyl, C₃-C₈        cycloalkyl, C₄-C₈ heterocycloalkyl, —(C₁-C₆ alkylene)(C₃-C₈        cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), -(C₁-C₆        alkylene)(C₄-C₈ heterocycloalkyl), —(C₃-C₈ cycloalkylene)(C₄-C₈        heterocycloalkyl), or O-aryl, or —O—(C₁-C₆ alkylene)aryl;        wherein said aryl, C₄-C₈ heterocycloalkyl, C₁-C₆ alkyl, C₃-C₈        cycloalkyl, C₃-C₈ cycloalkylene, and C₁-C₆ alkylene groups may        each independently be optionally substituted with from one to        six fluoro and may each independently be optionally substituted        with one or two substituents R₈ independently selected from the        group consisting of C₁-C₄ alkyl, —C₃-C₈ cycloalkyl, hydroxy,        fluoro, chloro, bromo, iodo, CF₃, —O—(C₁-C₆ alkyl), —O—(C₃-C₅        cycloalkyl), —O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄ alkyl),        —O—CO—N(R₂₄)(R₂₅), —N(R₂₄)(R₂₅), —S(C₁-C₄ alkyl), —S(C₃-C₅        cycloalkyl), —N(C₁-C₄alkyl)CO(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl),        —COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂        alkyl), CN, NO₂, —OSO₂(C₁-C₄ alkyl), S⁺(C₁-C₆ alkyl)(C₁-C₂        alkyl)I⁻, —SO(C₁-C₄ alkyl) and —SO₂(C₁-C₄ alkyl); and wherein        the C₁-C₆ alkyl, C₁-C₆ alkylene, C₅-C₈ cycloalkyl, C₅-C₈        cycloalkylene, and C₅-C₈ heterocycloalkyl moieties of R₁ may        optionally independently contain from one to three double or        triple bonds; and wherein the C₁-C₄ alkyl moieties and the C₁-C₆        alkyl moieties of R₈ can optionally independently be substituted        with hydroxy, C₁-C₄ alkyl, amino, aryl, —CH₂-aryl, —C₃-C₅        cycloalkyl, or —O—(C₁-C₄ alkyl), and can optionally        independently be substituted with from one to five fluoro, and        can optionally contain one or two double or triple bonds; and        wherein each heterocycloalkyl group of R₁ contains from one to        three heteromoieties selected from oxygen, S(O)_(m), nitrogen,        and NR₁₂;    -   R₂ is hydrogen, C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, C₄-C₈        heterocycloalkyl, —(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈        cycloalkylene)(C₃-C₈ cycloalkyl), —(C₁-C₆ alkylene)(C₄-C₈        heterocycloalkyl), —(C₃-C₈ cycloalkylene)(C₄-C₈        heterocycloalkyl), aryl, C₁-C₆ alkylene)aryl, or —(C₃-C₈        cycloalkylene)(aryl); wherein each of the foregoing R₂ groups        may optionally be substituted with from one three substituents        independently selected from chloro, fluoro, and C₁-C₆ alkyl,        wherein one of said one to three substituents can further be        selected from bromo, iodo, C₁-C₆ alkoxy, —OH, —O—CO—(C₁-C₆        alkyl), —O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₆ alkyl),        —S(O)(C₁-C₆ alkyl), —S(O)₂(C₁-C₆ alkyl), S⁺(C₁-C₆ alkyl)(C₁-C₂        alkyl)I⁻, CN, and NO₂; and wherein the C₁-C₁₂ alkyl, —(C₁-C₆        alkylene), —(C₅-C₈ cycloalkyl), —(C₅-C₈ cycloalkylene), and        —(C₅-C₈ heterocycloalkyl) moieties of R₂ may optionally        independently contain from one to three double or triple bonds;        and wherein each heterocycloalkyl group of R₂ contains from one        to three heteromoieties selected from oxygen, S(O)_(m),        nitrogen, and NR₁₂;    -   or where R₁ and R₂ are as in —NHCHR₁R₂, —OCHR₁R₂, —SCHR₁R₂,        —CHR₁R₂ or —NR₁R₂, R₁ and R₂ of B may form a saturated 5 to        8-membered ring which may optionally contain one or two double        bonds and in which one or two of the ring carbons may optionally        be replaced by an oxygen, S(O)_(m), nitrogen or NR₁₂; and which        carbocyclic ring can optionally be substituted with from 1 to 3        substituents selected from the group consisting of hydroxy,        C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, CF₃, —O—(C₁-C₄ alkyl),        —O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄ alkyl), —O—CO—N(C₁-C₄        alkyl)(C₁-C₂ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₂ alkyl)(C₁-C₄        alkyl), —S(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)CO(C₁-C₄ alkyl),        —NHCO(C₁-C₄ alkyl),—COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),        —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), CN, NO₂, —OSO₂(C₁-C₄ alkyl),        —SO(C₁-C₄ alkyl), and —SO₂(C₁-C₄ alkyl), wherein one of said one        to three substituents can further be selected from phenyl;    -   R₃ is methyl, ethyl, fluoro, chloro, bromo, iodo, cyano,        methoxy, OCF₃, NH₂, NH(C₁-C₂ alkyl), N(CH₃)₂, —NHCOCF₃,        —NHCH₂CF₃, S(O)_(m)(C₁-C₄ alkyl), CONH₂, —CONHCH₃, CON(CH₃)₂,        —CF₃, or CH₂OCH₃;    -   R₄ is hydrogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl, —(C₁-C₄        alkylene)(C₃-C₅ cycloalkyl), —(C₃-C₅ cycloalkylene)(C₃-C₅        cycloalkyl), cyano, fluoro, chloro, bromo, iodo, —OR₂₄, C₁-C₆        alkoxy, —O—(C₃-C₅ cycloalkyl), -O-(C₁-C₄ alkylene) (C₃-C₅        cycloalkyl), —O—(C₃-C₅ cycloalkylene)(C₃-C₅ cycloalkyl),        —CH₂SC(S)O(C₁-C₄ alkyl), —CH₂OCF₃, CF₃, amino, nitro, —NR₂₄R₂₅,        —(C₁-C₄ alkylene)—OR₂₄, —(C₁-C₄ alkylene)Cl, —(C₁-C₄        alkylene)NR₂₄R₂₅, —NHCOR₂₄, —NHCONR₂₄R₂₅, —C═NOR₂₄, —NHNR₂₄R₂₅,        —S(O)_(m)R₂₄, —C(O)R₂₄, —OC(O)R₂₄, —C(O)CN, —C(O)NR₂₄R₂₅,        —C(O)NHNR₂₄R₂₅, and —COOR₂₄, wherein the alkyl and alkylene        groups of R₄ may optionally independently contain one or two        double or triple bonds and may optionally independently be        substituted with one or two substituents R₁₀ independently        selected from hydroxy, amino, —NHCOCH₃, —NHCOCH₂Cl, —NH(C₁-C₂        alkyl), —N(C₁-C₂ alkyl)(C₁-C₂ alkyl), —COO(C₁-C₄ alkyl), —COOH,        —CO(C₁-C₄ alkyl), C₁-C₆ alkoxy, C₁-C₃ thioalkyl, cyano and        nitro, and with one to four substituents independently selected        from fluoro and chloro;    -   R₅ is aryl or heteroaryl and is substituted with from one to        four substituents R₂₇ independently selected from halo, C₁-C₁₀        alkyl, —(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), —(C₁-C₄        alkylene)(C₄-C₈ heterocycloalkyl), —(C₃-C₈ cycloalkyl), —(C₄-C₈        heterocycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),        —(C₃-C₈ cycloalkylene)(C₄-C₈ heterocycloalkyl), C₁-C₄ haloalkyl,        C₁-C₄ haloalkoxy, nitro, cyano, —NR₂₄R₂₅, —NR₂₄COR₂₅,        —NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅, —CONR₂₄R₂₅, —CO(NOR₂₂)R₂₃, —CO₂R₂₆,        —C═N(OR₂₂)R₂₃, and —S(O)_(m)R₂₃; wherein said C₁-C₁₀ alkyl,        C₃-C₈ cycloalkyl, (C₁-C₄ alkylene), (C₃-C₈ cycloalkyl), (C₃-C₈        cycloalkylene), and (C₄-C₈ heterocycloalkyl) groups can be        optionally substituted with from one to three substituents        independently selected form C₁-C₄ alkyl, C₃-C₈ cycloalkyl,        (C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈        cycloalkyl), C₁-C₄ haloalkyl, hydroxy, C₁-C₆ alkoxy, nitro halo,        cyano, —NR₂₄R₂₅, —NR₂₄COR₂₅, NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅,        —CONR₂₄R₂₅, CO₂R₂₆, —CO(NOR₂₂)R₂₅, and —S(O)_(m)R₂₃; and wherein        two adjacent substituents of the R₅ group can optionally form a        57 membered ring, saturated or unsaturated, fused to R⁵, which        ring optionally can contain one, two, or three heterologous        members independently selected from O, S(O)_(m), and N, but not        any —S—S—, —O—O—, —S—O—, or —N—S— bonds, and which ring is        optionally substituted with C₁-C₄ alkyl, C₃-C₈ cycloalkyl, C₁-C₄        alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cyloalkylene)(C₃-C₈        cycloalkyl), C₁-C₄ haloalkyl, nitro, halo, cyano —NR₂₄R₂₅,        NR₂₄COR₂₅, NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅, —CONR₂₄R₂₅, CO₂R₂₆,        —CO(NOR₂₆)R₂₅, or —S(O)_(m)R₂₃; wherein one of said one to four        optional substituents R₂₇ can further be selected from        —SO₂NH(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl),        —SO₂NH(C₃-C₈ cycloalkyl), —SO₂NH(C₃-C₈ cycloalkylene)(C₃-C₈        cycloalkyl), —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO₂NH₂,        —NHSO₂(C₁-C₄ alkyl), —NHSO₂(C₃-C₈ cycloalkyl), —NHSO₂(C₁-C₄        alkylene)(C₃-C₈ cycloalkyl), and —NHSO₂(C₃-C₈        cycloalkylene)(C₃-C₈ cycloalkyl); and wherein the alkyl, and        alkylene groups of R₅ may independently optionally contain one        double or triple bond;    -   R₆ is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, —(C₁-C₆        alkylene)(C₃-C₈ cycloalkyl), or C₃-C₈ cycloalkylene)(C₃-C₈        cycloalkyl), wherein said alkyl and cycloalkyl may optionally be        substituted with one hydroxy, methoxy, ethoxy or fluoro group;    -   or, wherein the compound is a compound of formula II, R₆ and R₄        can together form an oxo (═O) group or can be connected to form        a 38 membered carbocyclic ring, optionally containing one to        three double bonds, and optionally containing one, two, or three        heterologous ring members selected from O, SO_(m), N, and NR₁₂,        but not containing any —O—O—, —S—O—, —S—S—, or —N—S— bonds, and        further optionally substituted with C₁-C₄ alkyl or C₃-C₈        cycloalkyl, wherein said C₁-C₄ alkyl substituent may optionally        contain one double or triple bond;    -   R₇ is hydrogen, methyl, fluoro, chloro, bromo, iodo, cyano,        hydroxy, —O(C₁-C₂ alkyl), —O(cyclopropyl), —COO(C₁-C₂ alkyl),        —COO(C₃-C₈ cycloalkyl), —OCF₃, CF₃, —CH₂OH, or CH₂OCH₃;    -   R₁₁ is hydrogen, hydroxy, fluoro, ethoxy, or methoxy;    -   R₁₂ is hydrogen or C₁-C₄ alkyl;    -   R₁₆ and R₁₇ are each, independently, hydrogen, hydroxy, methyl,        ethyl, methoxy, or ethoxy, except that R₁₆ and R₁₇ are not both        methoxy or ethoxy;    -   or R₁₆ and R₁₇ together form an oxo (═O) group;    -   or R₁₆ and R₁₇ are connected to form a 3-8 membered carbocyclic        ring, optionally containing one to three double bonds, and        optionally containing from one to three heterologous ring        members selected from O, SO_(m), N, and NR₁₂, but not containing        any —O—O—, —S—O—, —S—S—, or —N—S— bonds, and further optionally        substituted with C₁-C₄ alkyl or C₃-C₆ cycloalkyl, wherein said        C₁-C₄ alkyl substituent may optionally contain one double or        triple bond;    -   R₂₂ is independently at each occurrence selected from hydrogen,        C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        C₃-C₈ cycloalkyl, (C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), and        (C₁-C₄ alkylene)(C₃-C₈ cycloalkyl);    -   R₂₃ is independently at each occurrence selected from C₁-C₄        alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₈ cycloalkyl,        —(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈        cycloalkylene)(C₃-C₈ cycloalkyl), aryl, —(C₁-C₄ alkylene)aryl,        piperidine, pyrrolidine, piperazine, N-methylpiperazine,        morpholine, and thiomorpholine;    -   R₂₄ and R₂₅ are independently at each occurrence selected from        hydrogen, —C₁-C₄ alkyl, C₁-C₄ haloalkyl, especially CF₃, —CHF₂,        CF₂CF₃, or CH₂CF₃, —(C₁-C₄ alkylene)OH, —(C₁-C₄        alkylene)—O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)—O—(C₃-C₅        cycloalkyl), C₃-C₈ cycloalkyl, —(C₁-C₄ alkylene)(C₃-C₈        cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), —(C₄-C₈        heterocycloalkyl), —(C₁-C₄ alkylene)(C₄-C₈ heterocycloalkyl),        —(C₃-C₈ cycloalkylene)(C₄-C₈ heterocycloalkyl), aryl, and        —(C₁-C₄ alkylene)(aryl), wherein the —C₄-C₈ heterocycloalkyl        groups can each independently optionally be substituted with        aryl, CH₂-aryl, or C₁-C₄ alkyl, and can optionally contain one        or two double or triple bonds; or, when R₂₄ and R₂₅ are as        NR₂₄R₂₅, —C(O)NR₂₄R₂₅, —(C₁-C₄ alkylene)NR₂₄R₂₅, or        —NHCONR₂₄R₂₅, then NR₂₄R₂₅ may further optionally form a 4 to 8        membered heterocyclic ring optionally containing, one or two        further hetero members independently selected from S(O)m,        oxygen, nitrogen, and NR,₂, and optionally containing from one        to three double bonds;    -   R₂₆ is independently at each occurrence selected from C₁-C₄        alkyl, C₁-C₄ haloalkyl, C₃-C₈ cycloalkyl, —(C₁-C₄        alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈        cycloalkyl), aryl, and - (C₁-C₄ alkylene)(aryl); and    -   wherein each m is independently zero, one, or two,    -   with the proviso that heterocycloalkyl groups of the compound of        formula I, II, or III do not comprise any —S—S—, —S—O—, —N—S—,        or —O—O— bonds, and do not comprise more than two oxygen or        S(O)_(m) heterologous members.

In one embodiment of the invention, the compound of the invention is offormula

wherein

-   -   the dashed lines represent optional double bonds;    -   A is —CR₇ or N;    -   B is —NR₁R₂, —CR₁R₂R₁₁, —C(═CR₂R₁₂)R₁, —NHCHR₁R₂, —OCHR₁R₂,        —SCHR₁R₂, —CHR₂OR₁₂, —CHR₂SR₁₂, —C(S)R₂ or —C(O)R₂;    -   G is oxygen, sulfur, NH, NH₃, hydrogen, methoxy, ethoxy,        trifluoromethoxy, methyl, ethyl, thiomethoxy, NH₂, NHCH₃,        N(CH₃)₂ or trifluoromethyl;    -   Y is —CH or N;    -   Z is NH, O, S, —N(C₁-C₂ alkyl) or —C(R₁₃R₁₄), wherein R₁₃ and        R₁₄ are each, independently, hydrogen, trifluoromethyl or        methyl, or one of R₁₃ and R₁₄ is cyano and the other is hydrogen        or methyl;    -   R₁ is C₁-C₆ alkyl which may optionally be substituted with one        or two substituents R₈ independently selected from the group        consisting of hydroxy, fluoro, chloro, bromo, iodo, CF₃, C₁-C₄        alkoxy, —O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄ alkyl),        —O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₂        alkyl)(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —N(C₁-C₄alkyl)CO(C₁-C₄        alkyl), —NHCO(C₁-C₄ alkyl), —COO(C₁-C₄ alkyl), —CONH(C₁-C₄        alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), CN, NO₂, —SO(C₁-C₄        alkyl) and —SO₂(C₁-C₄ alkyl), and wherein said C₁-C₆ alkyl and        the (C₁-C₄)alkyl moieties in the foregoing R₁ groups may        optionally contain one carbon-carbon double or triple bond;    -   R₂ is C₁-C₁₂ alkyl, aryl or —(C₁-C₄ alkylene)aryl wherein said        aryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,        quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl,        benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl,        benzisoxazolyl, benzimidazolyl, indolyl, or benzoxazolyl; 3- to        8-membered cycloalkyl or —(C₁-C₆ alkylene)cycloalkyl, wherein        one or two of the ring carbons of said cycloalkyl having at        least 4 ring members and the cycloalkyl moiety of said —(C₁-C₆        alkylene)cycloalkyl having at least 4 ring members may        optionally be replaced by an oxygen or sulfur atom or by N-R₉        wherein R₉ is hydrogen or C₁-C₄ alkyl; and wherein each of the        foregoing R₂ groups may optionally be substituted with from one        to three substituents independenty selected from chloro, fluoro        and C₁-C₄ alkyl, or with one substituent selected from bromo,        iodo, C₁-C₆ alkoxy, —O—CO—(C₁-C₆ alkyl), —O—CO—N(C₁-C₄        alkyl)(C₁-C₂ alkyl), —S(C₁-C₆ alkyl), CN, NO₂, —SO(C₁-C₄ alkyl),        and —SO₂(C₁-C₄ alkyl), and wherein said C₁-C₁₂ alkyl and the        C₁-C₄ alkylene moiety of said —(C₁-C₄ alkylene)aryl may        optionally contain one carbon-carbon double or triple bond;    -   or —NR₁R₂ or —CR₁R₂R₁₁ may form a saturated 5- to 8-membered        carbocyclic ring which may optionally contain one or two        carbon-carbon double bonds and in which one or two of the ring        carbons may optionally be replaced by an oxygen or sulfur atom;    -   R₃ is methyl, ethyl, fluoro, chloro, bromo, iodo, cyano,        methoxy, OCF₃, methylthio, methylsulfonyl, CH₂OH, or CH₂OCH₃;    -   R₄ is hydrogen, C₁-C₄ alkyl, fluo, bromo, iodo, C₁-C₄ alkoxy,        trifluoromethoxy, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃, —CH₂OF₃,        CF₃, amino, nitro, —NH(C₁-C₄ alkyl), —N(CH₃)₂, —NHCOCH₃,        —NHCONHCH₃, —SO_(n)(C₁-C₄ alkyl) wherein n is 0, 1 or 2, cyano,        hydroxy, —CO(C₁-C₄ alkyl), —CHO, cyano or —COO(C₁-C₄ alkyl)        wherein said C₁-C₄ alkyl may optionally contain one double or        triple bond and may optionally be substituted with one        substituent selected from hydroxy, amino, —NHCOCH₃, —NH(C₁-C₂        alkyl), —N(C₁-C₂ alkyl)₂, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        C₁-C₃ alkoxy, C₁-C₃ thioalkyl, fluoro, chloro, cyano and nitro;    -   R₅ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,        quinolyl, pyrazinyl, pyrimidyl, furanyl, benzofuranyl,        benzothiazolyl, or indolyl, wherein each of the above groups R₅        is substituted with from one to three substituents independently        selected from fluoro, chloro, C₁-C₆ alkyl, and C₁-C₆ alkoxy, or        with one substituent selected from hydroxy, iodo, bromo, formyl,        cyano, nitro, trifluoromethyl, amino,—(C₁-C₆        alkyl)O(C₁-C₆)alkyl, —NHCH₃, —N(CH₃), —COOH, —COO(C₁-C₄ alkyl),        —CO(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄ alkyl)(C₁-C₂        alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₆ alkyl) and        —SO₂(C₁-C₆ alkyl), and wherein the C₁-C₄ alkyl and C₁-C₆ alkyl        moieties of the foregoing R₅ groups may optionally be        substituted with one or two fluoro groups or with one        substituent selected from hydroxy, amino, methylamino,        dimethylamino and acetyl;    -   R₆ is hydrogen or C₁-C₆ alkyl, wherein said C₁-C₆ alkyl may        optionally be substituted with one hydroxy, methoxy, ethoxy or        fluoro group;    -   R₇ is hydrogen, methyl, fluoro, chloro, bromo, iodo, cyano,        hydroxy, —O(C₁-C₄ alkyl), —C(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄        alkyl), —OCF₃, CF₃, —CH₂OH, —CH₂OCH₃ or —CH₂OCH₂CH₃;    -   R₁₁ is hydrogen, hydroxy, fluoro, or methoxy;    -   R₁₂ is hydrogen or C₁-C₄ alkyl; and    -   R₁₆ and R₁₇ are each, independently, hydrogen, hydroxy, methyl,        ethyl, methoxy, or ethoxy, except that R₁₆ and R₁₇ are not both        methoxy or ethoxy;    -   or R₁₆ and R₁₇ together form an oxo (═O) group;    -   with the proviso that when G is oxygen, sulfur, NH or NCH₃, it        is double bonded to the five membered ring of structure III, and        with the further proviso that R₆ is absent when the nitrogen to        which it is attached is double bonded to an adjacent ring carbon        atom;    -   or a pharmaceutically acceptable salt of such compound.

More specific embodiments of this invention include compounds of theformula I, II or III wherein: (a) B is —NR₁R₂, —NHCHR₁R₂, —SCHR₁R₂ orOCHR₁R₂; R₁ is C₁-C₆ alkyl, which may optionally be substituted with onehydroxy, fluoro, CF₃, or C₁-C₂ alkoxy group and may optionally containone double or triple bond; and R₂ is benzyl or C₁-C₆ alkyl which mayoptionally contain one carbon-carbon double or triple bond, wherein saidC₁-C₆ alkyl or the phenyl moiety of said benzyl may optionally besubstituted with fluoro, CF₃, C₁-C₂ alkyl, or C₁-C₂ alkoxy; or (b) B is—CR₁R₂R₁₁ wherein R₁ is C₁-C₆ alkyl which may optionally be substitutedwith one Cl-C₂ alkoxy, CF₃, fluoro or hydroxy group; R₂ is benzyl orC₁-C₆ alkyl wherein said C₁-C₆ alkyl or the phenyl moiety of said benzylmay optionally be substituted with one C₁-C₂ alkyl, CF₃, C₁-C₂ alkoxy,fluoro, chloro or bromo group; and R₁₁ is hydrogen or fluoro.

Other more specific embodiments of this invention include compounds ofthe formula I, II or III wherein R₁ is C₁-C₆ alkyl which may optionallybe substituted by fluoro, CF₃, hydroxy, C₁-C₂ alkyl or C₁-C₂ alkoxy andmay optionally contain one carbon-carbon double or triple bond, and R₂is C₁-C₄ alkyl which may optionally be substituted with fluoro, chloro,CF₃, C₁-C₄ alkyl or C₁-C₄ alkoxy.

Other more specific embodiments of this invention include compounds ofthe formula I, II or III wherein R₃ is methyl, chloro, or methoxy, R₄ ismethyl, —CH₂OH, cyano, trifluoromethoxy, methoxy, trifluoromethyl,chloro, —COOCH₃, —CH₂OCH₃, —CH₂Cl, —CH₂F, amino or nitro; R₆ ishydrogen, methyl or ethyl and R₅ is phenyl or pyridyl wherein saidphenyl or pyridyl is substituted by two or three substituentsindependently selected from fluoro, chloro, bromo, iodo, C₁-C₄ alkoxy,trifluoromethyl, C₁-C₆ alkyl which may optionally be substituted withone hydroxy, C₁-C₂ alkoxy or fluoro group and may optionally contain onecarbon-carbon double or triple bond, —(C₁-C₄ alkylene)O(C₁-C₂ alkyl),C₁-C₃ hydroxyalkyl, hydroxy, formyl, —COO(C₁-C₂ alkyl), —(C₁-C₂alkylene)amino, and —(C(O)(C₁-C₄ alkyl).

Examples of preferred compounds of this invention are:

-   -   4-(1        -ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine;    -   2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   2-(2,6-dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;    -   2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   4-(1-methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-diethyl-amine;    -   [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine;    -   [2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-propyl)-amine;    -   butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;    -   4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridine;    -   butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   [3,6-dimethyl-[2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-ethyl-propyl-amine;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-propyl-amine;    -   1-(ethyl-propyl)-[6-ethyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;    -   N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine;    -   N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;    -   N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine;    -   [3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4yl]-(1-ethyl-propyl)-amine;    -   [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   (1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-pyrimidin-4-yl]-amine;    -   (1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;    -   (N-(1-ethyl-propyl)-2-methyl-5-nitro-N′-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,6-diamine;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-diethyl-amine;    -   4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine;    -   butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethyl-amine;    -   4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one;    -   4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine;    -   N-butyl-N-ethyl-2,5-dimethyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine;    -   (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amine;    -   [2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;    -   N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine;    -   [4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;        and    -   6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihydro-purin-8-one.

Other preferred compounds of this invention are:

-   -   4-(1-ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine;    -   2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   2-(2,6-dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;    -   2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;    -   4-(1-methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-diethyl-amine;    -   [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine;    -   [2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-propyl)-amine;    -   butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;    -   4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridine;    -   butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   [3,6-dimethyl-[2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-ethyl-propyl-amine;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-propyl-amine;    -   1-(ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;    -   N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine;    -   N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;    -   N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine;    -   [3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   (1-ethyl-propyl)-[2-methyl-5nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-pyrimidin-4-yl]-amine;    -   (1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;    -   (N-(1-ethyl-propyl)-2-methyl-5-nitro-N′-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,6-diamine;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-diethyl-amine;    -   4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine;    -   butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethyl-amine;    -   4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one;    -   4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine;    -   N-butyl-N-ethyl-2,5-dimethyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine;    -   (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amine;    -   [2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;    -   N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine;    -   [4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine;        and    -   6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihydro-purin-8-one        .

Examples of preferred compounds of this invention are:

-   -   2-[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-(S)-ylamino]-butan-1-ol;    -   (1-methoxymethyl-propyl)-[6-methyl-3-nitro-2-(4-trifluoromethoxy-phenoxy)-pyridin-4-yl]-amine;    -   2-(2-amino-4,6-dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   3-methoxy-2-[4-(1-methoxymethyl-propylamino)-6-methyl-3-nitro-pyridin-2-yloxy]-benzaldehyde;    -   [2-(2,6-dibromo-4-trifluoromethoxy-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   [2-(2-bromo-4-chloro-6-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   [2-(2,4-dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   [2-(2-bromo-6-chloro-4-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   (1-methoxymethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine;    -   2-chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide;    -   3-chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-propionamide;    -   2-chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-propionamide;    -   N3-allyl-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   N3-(3-chloro-propyl)-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   N4-(1-ethyl-propyl)-6-methyl-N3-propa-1,2-dienyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;    -   2-[3-amino-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   4-(1-ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   2-(4-bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2-methoxy-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-yl)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-[(2-hydroxy-ethylamino)-methyl]-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   4-[ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   4-[ethyl-(2-methanesulfonyloxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   4-[(2-hydroxy-ethyl)-thiophen-2-ylmethyl-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   4-(2,2-dimethyl-4-phenyl-[1,3]dioxan-5-ylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic        acid ethyl ester;    -   4-[ethyl-(2-methoxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S,R)-&(S,S)-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(R)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   4-(2-hydroxy-1-hydroxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   4-(2-methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   4-(1-hydroxymethyl-2-methoxy-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-butylamino)-6-methyl-nicotinic        acid methyl ester;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol;    -   [2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol;    -   2-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-ol;    -   3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-pentan-2-ol;    -   2-[2-(2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol;    -   3-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-pentan-2-ol;    -   2-[2-(4-chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol;    -   2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol;    -   2ethyl-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amino)-ethanol;    -   4-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-hexan-3-ol;    -   2-[2-(4-chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   4-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-hexan-3-ol;    -   [2-(2,4-dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic        acid;    -   4-(1-ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid;    -   2-(4-bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6-methyl-nicotinic        acid;    -   4-(2-methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic        acid;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3-isobutoxymethyl-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   [3-ethoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   2-[3-butoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butan-1-ol;    -   1-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-ethanol;    -   acetic acid        4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl        ester;    -   2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   [2-(2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   4-[4-(1-ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy[-3,5-dimethyl-benzaldehyde;    -   {4-[4-(1-ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl)-methanol;    -   (1-ethyl-propyl)-[2-(4-methoxymethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine;    -   [2-(4-ethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   2-{4-[4-(1-ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl)-propan-2-ol;    -   1-{4-[4-(1-ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl)-ethanol;    -   (1-ethyl-propyl)-[2-(4-isopropenyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine;    -   (1-ethyl-propyl)-[2-(4-isopropyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine;    -   [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-        allyl)-amine;    -   (1-ethyl-propyl)-[2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine;    -   2-[2-(2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-butan-1-ol;    -   2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-ol;    -   3-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-pentan-2-ol;    -   3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pentan-2-ol;    -   benzyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-3-phenyl-propan-1-ol;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethoxymethyl-propyl)-amine;    -   [3,6-dimethyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   [2-(4-bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethy-propyl)-amine;    -   (1-ethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   [2-(4-bromo-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   (1-ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;    -   [2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   [2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   [2-(4-chloro-2-methoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   [2-(3-chloro-2,6-dimethoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   (1-methoxymethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine;    -   [3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-yl]-(1-ethoxymethyl-propyl)-amine;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3-ethoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   2-(2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   2-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1ol;    -   2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-ylamino]-butan-1-ol;    -   4-[4-(1-hydroxymethyl-propylamino)-3-methoxy-6-methyl-pyridin-2-yloxy]-3,5-dimethyl-benzonitrile;    -   3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pentan-2-ol;    -   2-[2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butan-1-ol;    -   (1-ethyl-prop-2-ynyl)-[2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine];    -   2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-ol;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol;    -   4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-pyridin-3-ol;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-ol;    -   chloro-acetic acid        4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl        ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-[(1-ethyl-propyl)-methyl-amino]-6-methyl-pyridin-3-ol;    -   [4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetonitrile;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehyde;    -   (1-ethyl-propyl)-[3-[(1-ethyl-propylimino)-methyl]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;    -   2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonic        acid dimethyl ester;    -   2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonic        acid diisopropyl ester;    -   4-(1-ethyl-propoxy)-6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine;    -   [4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-        3-yl]-dimethyl-amine;    -   N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethy-phenoxy)-pyridin-3-yl]-succinamic        acid;    -   4-(1-ethyl-propoxy)-3,6-dimethyl-2-[3-(2,4,6-trimethyl-pyridinoxy)]-pyridine;    -   6-ethyl-4-(1-ethyl-propoxy)-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   4-(1-ethyl-propoxy)-2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;    -   [4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine;    -   [4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol;    -   [4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-oxo-acetonitrile;    -   [4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-imidazol-1-yl-methanone;    -   2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-propan-2-ol;    -   2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic        acid dimethyl ester;    -   3-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-propionic        acid;    -   [3-aminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine;    -   2-chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-acetamide;    -   [3-dimethylaminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine        hydrochloride salt;    -   dithiocarbonic acid O-ethyl ester        S-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]        ester;    -   4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide;    -   4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinonitrile;    -   4-(1-ethyl-propoxy)-6,N,N-trimethyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide;    -   [4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-acetonitrile;    -   [2-(4-bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;    -   [2-(4-chloro-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;    -   [2-(2,4-dichloro-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;    -   [2-(2,4-dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;    -   [4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone;    -   1-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-ethanone;    -   (1-ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;    -   2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-2-methyl-malonic        acid dimethyl ester;    -   [4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine;    -   2-ethyl-1-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butan-1-ol;    -   1-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2-methyl-butan-1-ol;    -   1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol;    -   4-(1-methoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   4-(1-ethoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   4-(1-allyloxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   4-(1-butoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   1-[2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-ol;    -   1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2,2,2-trifluoro-ethanol;    -   1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trifluoro-ethanol;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyridin-2-yl-methanol;    -   1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-ol;    -   1-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-one;    -   1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trifluoro-ethanone;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyridin-2-yl-methanone;    -   1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one;    -   4-(1-ethoxy-2,2,2-trifluoro-ethyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;    -   2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butan-2-ol;    -   3-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-pentan-3-ol;    -   1-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinamide;    -   4-(1-ethyl-propylamino)-6,N-dimethyl-2-(2,4,6-trimethyl-phenoxy)-nicotinamide;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic        acid hydrazide;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-N-ethyl-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6,N-dimethyl-nicotinamide;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-N-cyclopentyl-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-N-cyctopropylmethyl-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide;    -   4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylic        acid amide;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinonitrile;    -   [4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine;    -   4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine;    -   2-chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-acetamide;    -   N-butyl-N-ethyl-6-methyl-3-nitro-N-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic        acid;    -   4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic        acid methyl ester;    -   N4-(1-ethyl-propyl)-3,6-dimethyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine;    -   2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic        acid dimethyl ester;    -   [2-(4-bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol;    -   N2-(2,4-dichloro-phenyl)-N4-(1-ethyl-propyl)-3,6-dimethyl-pyridine-2,4-diamine;    -   [2-(2,4-dichloro-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol;    -   2-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenylamino)-pyridin-4-ylamino]-butan-1-ol;    -   2-[4-(1-ethyl-propylamino)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-5-yl]-propionic        acid ethyl ester;    -   [3-aminomethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   [2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-acetonitrile;    -   [2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-acetonitrile        hydrogen chloride;    -   [6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine;    -   2-[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   [3-aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-yl]-(1-chloromethyl-propyl)-amine;    -   2-[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-3-methylaminomethyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   2-[3-aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   [3-bromo-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;    -   2-[3,5-dibromo-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylamino]-butan-1-ol;    -   2-[3-bromo-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   2-[3-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   2-[3,5-dichloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylamino]-butan-1-ol;    -   2-[3-chloro-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-ylamino]-butan-1-ol;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-yl)-6-methyl-nicotinonitrile;    -   2-(2,4-dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinic        acid;    -   4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carbonitrile;    -   N-(1-ethyl-propyl)-2,5-dimethyl-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine;    -   5-chloro-N4-(1-ethyl-propyl)-2-methyl-N6-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine;    -   5-bromo-N-(1-ethyl-propyl)-2-methyl-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine;    -   4-(1-ethyl-propylamino)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylic        acid;    -   [4-(cyclopropylmethyl-propyl-amino)-2-methyl-6-(2,4,6-trichloro-phenylamino)-pyrimidin-5-yl]-methanol;    -   6-(1-ethyl-propoxy)-2,N5,N5-trimethyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine;    -   [5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl-(2,4,6-trimethyl-phenyl)-amine;    -   4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylic        acid;    -   [4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-methanol;    -   [6-(1-ethyl-propoxy)-5-methoxymethyl-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine;    -   [5-aminomethyl-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine;    -   4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carbonitrile;    -   7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-2-ylamine;    -   7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridine;    -   7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;    -   7-(1-ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one;    -   (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amine;    -   [2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;    -   N7-(1-ethyl-propyl)-5-methyl-3-(2,4,6-trimethyl-phenyl        )-3H-imidazo[4,5-b]pyridine-2,7-diamine;    -   6-(1-ethyl-propylamino)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one;    -   6-(1-ethyl-propoxy)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one;    -   [2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine;    -   (1-ethyl-propyl)-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine;    -   2-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-butan-1-ol;    -   sec-butyl-[3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-yl]-amine;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(4-ethyl-oxazolidin-3-yl)-3,6-dimethyl-pyridine;    -   4-(4-ethyl-oxazolidin-3-yl)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;    -   2-(4-methoxy-2,6-dimethyl-phenoxy)-N%4&-(1-methoxymethyl-propyl)-6-methyl-pyridine-3,4-diamine;    -   3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-pentan-2-ol;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxymethyl-6-methyl-pyridin-4-ylamino]-pentan-2-ol;    -   3-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pentan-2-ol;    -   4-sec-butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-2-methyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   4-(1-hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinic        acid methyl ester;    -   2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinic        acid methyl ester;    -   {3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxycarbonyl-6-methyl-pyridin-4-ylamino]-4-hydroxy-butyl}-dimethyl-sulfonium        iodide;    -   4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinic        acid methyl ester;    -   4-(1-hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide;    -   4-sec-butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide;    -   2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinic        acid methyl ester;    -   4-sec-butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinamide;        and        and pharmaceutically acceptable salts thereof.

The invention also relates to a pharmaceutical composition for thetreatment of (a) a disorder or condition the treatment of which can beeffected or facilitated by antagonizing CRF, including but not limitedto disorders induced or facilitated by CRF, or (b) a disorder orcondition selected from inflammatory disorders such as rheumatoidarthritis and osteoarthritis, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic; phobias, including social phobia,agoraphobia, and specific phobias; obsessive-compulsive disorder;post-traumatic stress disorder; sleep disorders induced by stress; painperception such as fibromyalgia; mood disorders such as depression,including major depression, single episode depression, recurrentdepression, child abuse induced depression, mood disorders associatedwith premenstrual syndrome, and postpartum depression; dysthemia;bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-inducedheadache; cancer, irritable bowel syndrome, Crohn's disease; spasticcolon; post operative ileus; ulcer; diarrhea; stress-induced fever;human immunodeficiency virus infections; neurodegenerative diseases suchas Alzheimer's disease, Parkinson's disease and Huntington's disease;gastrointestinal diseases; eating disorders such as anorexia and bulimianervosa; hemorrhagic stress; chemical dependencies or addictions,including dependencies or addictions to alcohol, cocaine, heroin,benzodiazapines, or other drugs; drug or alcohol withdrawal symptoms;stress-induced psychotic episodes; euthyroid sick syndrome; syndrome ofinappropriate antidiuretic hormone; obesity; infertility; head trauma;spinal cord trauma; ischemic neuronal damage, including cerebralischemia, for example cerebral hippocampal ischemia; excitotoxicneuronal damage; epilepsy; stroke; immune dysfunctions including stressinduced immune dysfunctions, including porcine stress syndrome, bovineshipping fever, equine paroxysmal fibrillation, confinement dysfunctionin chicken, sheering stress in sheep, and human-animal interactionstress in dogs; muscular spasms; urinary incontinence; senile dementiaof the Alzheimer's type; multiinfarct dementia; amyotrophic lateralsclerosis; hypertension; tachycardia; congestive heart failure;osteoporosis; premature birth; hypoglycemia, and Syndrome X in a mammal,including a human, or bird comprising an amount of a compound of theformula I, II or III, or a pharmaceutically acceptable salt thereof,that is effective in the treatment of such disorder or condition, and apharmaceutically acceptable carrier.

The invention further includes a method for the treatment of (a) adisorder or condition the treatment of which can be effected orfacilitated by antagonizing CRF, including but not limited to disordersinduced or facilitated by CRF, or (b) a disorder or condition selectedfrom inflammatory disorders such as rheumatoid arthritis andosteoarthritis, pain, asthma, psoriasis and allergies; generalizedanxiety disorder; panic; phobias, including social phobia, agoraphobia,and specific phobias; obsessive-compulsive disorder; post-traumaticstress disorder; sleep disorders induced by stress; pain perception suchas fibromyalgia; mood disorders such as depression, including majordepression, single episode depression, recurrent depression, child abuseinduced depression, mood disorders associated with premenstrualsyndrome, and postpartum depression; dysthemia; bipolar disorders;cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer;irritable bowel syndrome, Crohn's disease; spastic colon; post operativeileus; ulcer; diarrhea; stress-induced fever; human immunodeficiencyvirus infections; neurodegenerative diseases such as Alzheimer'sdisease, Parkinson's disease and Huntington's disease; gastrointestinaldiseases; eating disorders such as anorexia and bulimia nervosa;hemorrhagic stress; chemical dependencies or addictions, includingdependencies or addictions to alcohol, cocaine, heroin, benzodiazapines,or other drugs; drug or alcohol withdrawal symptoms; stress-inducedpsychotic episodes; euthyroid sick syndrome; syndrome of inappropriateantidiuretic hormone; obesity; infertility; head trauma; spinal cordtrauma; ischemic neuronal damage, including cerebral ischemia, forexample cerebral hippocampal ischemia; excitotoxic neuronal damage;epilepsy; stroke; immune dysfunctions including stress induced immunedysfunctions, including porcine stress syndrome, bovine shipping fever,equine paroxysmal fibrillation, confinement dysfunction in chicken,sheering stress in sheep, and human-animal interaction stress in dogs;muscular spasms; urinary incontinence; senile dementia of theAlzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis;hypertension; tachycardia; congestive heart failure; osteoporosis;premature birth; hypoglycemia, and Syndrome X in a mammal, including ahuman, or bird comprising administering to a subject in need of saidtreatment an amount of a compound of the formula I, II or III or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disorder or condition.

Specific embodiments of the invention provide a pharmaceuticalcomposition and a method for treatment of (a) a disorder the treatmentof which can be effected or facilitated by antagonizing CRF, includingbut not limited to disorders induced or facilitated by CR, or (b) adisorder selected from inflammatory disorders such as rheumatoidarthritis and osteoarthritis, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder, sleep disorders induced bystress; pain perception such as fibromyalgia; mood disorders such asdepression, including major depression, single episode depression,recurrent depression, child abuse induced depression, and postpartumdepression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome;stress-induced headache; cancer; irritable bowel syndrome, Crohn'sdisease; spastic colon; human immunodeficiency virus (HIV) infections;neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and Huntington's disease; gastrointestinal diseases; eatingdisorders such as anorexia and bulimia nervosa; hemorrhagic stress;chemical dependencies and addictions (eg, dependencies on alcohol,cocaine, heroin, benzodiazepines, or other drugs); drug and alcoholwithdrawal symptoms; stress-induced psychotic episodes; euthyroid sicksyndrome; syndrome of inappropriate antidiuretic hormone (ADH); obesity;infertility; head traumas; spinal cord trauma; ischemic neuronal damage(eg., cerebral ischemia such as cerebral hippocampal ischemia);excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctionsincluding stress induced immune dysfunctions (e.g, porcine stresssyndrome, bovine shipping fever, equine paroxysmal fibrillation, anddysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs); muscularspasms; urinary incontinence; senile dementia of the Alzheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; and hypoglycemiain a mammal, including a human.

The present invention also provides a pharmaceutical composition for anda method of treating a condition comprising administering a compound ofI, II, or III, in an amount effective to treat said condition, whereinsaid condition is selected from the group consisting of: a) abnormalcircadian rhythm; b) depression, further wherein a second compound fortreating depression is administered, said second compound for treatingdepression having an onset of action that is delayed with respect tothat of said CRF antagonist; and c) emesis. The aforementioned methodcan practiced according to the information provided in U.S. ProvisionalPatent Application No. 60/151,183, filed Aug. 27, 1999, which describestreatment of the aforementioned conditions using CRF antagonists ingeneral and which is incorporated herein by reference in its entirety.

The compounds of formula I, II, and III, described herein can also beused to treat forms of heart failure described in U.S. Ser. No.09/248,073, supra, and can be made into pharmaceutical compositionstherefore.

Examples of more specific forms or manifestations of abnormal circadianrhythm that can be treated according to the present invention include,but are not limited to, time zone change syndrome resulting, seasonaldisorder, shift-work sleep disorder, irregular sleep-wake pattern,delayed sleep phase syndrome resulting from said abnormal circadianrhythm, advanced sleep phase syndrome, or non-24 hour sleep wakedisorder resulting from said abnormal circadian rhythm. Moreover, thecompound of formula I, II, or III can be combined in the method orpharmaceutical composition for treatment of abnormal circadian rhythmwith a second compound that is useful for treating a sleep disorder, forexample tachykinin antagonists, agonists for GABA brain receptors,metalonergic compounds, GABA brain receptor agonists, 5HT₂ receptorantagonists, and D4 receptor binding compounds. However, other compoundsor substances useful for treating a sleep disorder can be combined witha compound of formula I, II, or III. Such methods and compositions aredescribed in greater detail in U.S. Provisional Patent Application No.60/151,183, supra.

In another embodiment, said condition is depression, and the secondcompound having delayed action for treating depression is selected fromthe group consisting of selective serotonin reuptake inhibitors,tricyclic antidepressants, norepinephrine uptake inhibitors, lithium,bupropion, sertraline, fluoxetine, trazodone, and a tricyclicantidepressant selected from the group consisting of imipramine,amitriptyline, trimipramine, doxepin, desipramine, nortriptyline,protriptyline, amoxapine, clomipramine, maprotiline, and carbamazepine,and pharmaceutically acceptable salts and esters of the above-recitedcompounds.

In another embodiment, the condition being treated is emesis, and themethod further comprises administering a second compound for treatingemesis. The second compound for treating emesis can be selected from,but is not limited to, tachykinin antagonists, 5HT3 antagonists, GABAagonists, and substance P inhibitors. More specific categories of emesisencompassed in the present invention include emesis induced by acondition or agent selected from the group consisting of pregnancy,vestibular disorder, post-operative sickness, gastrointestinalobstruction, reduced gastrointestinal motility, visceral pain, migraine,change in intercranial pressure, chemotherapy, radiation, toxins, andopioid analgesics.

The invention further includes intermediate compounds of formula

-   -   wherein R₄ and R₇ are defined as they are for formula I above; D        is chloro, hydroxy or cyano; R₁₉ is methyl or ethyl; R₅ is        phenyl or pyridyl and R₅ is substituted by two or three        substituents independently selected from C₁-C₄ alkyl, chloro and        bromo, except that no more than one such substituent can be        bromo; A is N, CH or CCH₃; and Z is O, NH, N(CH₃), S or CH₂,        with the proviso that when A is CH or CCH₃, then Z must be O or        S.

More specific embodiments of this invention relate to compounds of theformula X or XI wherein R₇ is hydrogen or methyl.

This invention further include intermediate compounds of formula

-   -   wherein R₁₉ is methyl or ethyl; A is N, CH or CCH₃; and wherein        when A is N, then B″ and R₄ are defined, respectively, as B and        R₄ are defined for formula I, and when A is CH or CH₃, then B″        is —NR₁R₂, —NHR₁R₂, —OCHR₁R₂ or cyano and R₄ is an electron        deficient group such as NO₂, —COO(C₁-C₄ alkyl), —C(═O)CH₃, —COOH        or CN.

A more specific embodiment of this invention relates to compounds of theformula XII wherein B″ is —NR₁R₂ or —NHCHR₁R₂ and A is CH or CH₃.

This invention also relates to a process for preparing a compound of theformula I,

or a pharmaceutically acceptable salt thereof, wherein

-   -   A is —CR₇ or N;    -   B is —NR₁R₂, —NHCHR₁R₂, —OCHR₁R₂ or —SCHR₁R₂;    -   Z is NH, O, S, —N(C₁-C₂ alkyl) or —C(R₁₃R₁₄), wherein R₁₃ and        R₁₄ are each, independently, hydrogen, trifluoromethyl or        methyl, or one of R₁₃ and R₁₄ is cyano and the other is hydrogen        or methyl;    -   R₁ is C₁-C₆ alkyl which may optionally be substituted with one        or two substituents R₈ independently selected from the group        consisting of hydroxy, fluoro, chloro, bromo, iodo, CF₃ and        C₁-C₄ alkoxy, and wherein said C₁-C₆ alkyl and the (C₁-C₄)alkyl        moiety of said C₁-C₄ alkoxy may optionally contain one        carbon-carbon double or triple bond;    -   R₂ is C₁-C₁₂ alkyl, aryl or —(C₁-C₄ alkylene)aryl wherein said        aryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,        quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl,        benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl,        benzisoxazolyl, benzimidazolyl, indolyl, or benzoxazolyl; 3- to        8-membered cycloalkyl or —(C₁-C₆ alkylene)cycloalkyl, wherein        one or two of the ring carbons of said cycloalkyl having at        least 4 ring members and the cycloalkyl moiety of said —(C₁-C₆        alkylene)cycloalkyl having at least 4 ring members may        optionally be replaced by an oxygen or sulfur atom or by N-R₉        wherein R₉ is hydrogen or C₁-C₄ alkyl; and wherein each of the        foregoing R₂ groups may optionally be substituted with from one        to three substituents independently selected from chloro, fluoro        and C₁-C₄ alkyl, or with one substituent selected from bromo,        iodo, C₁-C₆ alkoxy, —O—CO—(C₁-C₆ alkyl), —O—CO—N(C₁-C₄        alkyl)(C₁-C₂ alkyl), —S(C₁-C₆ alkyl), CN, NO₂, —SO(C₁-C₄ alkyl),        and —SO₂(C₁-C₄ alkyl), and wherein said C₁-C₁₂ alkyl and the        C₁-C₄ alkylene moiety of said —(C₁-C₄ alkylene)aryl may        optionally contain one carbon-carbon double or triple bond;    -   or —NR₁R₂ may form a saturated 5 to 8-membered carbocyclic ring        which may optionally contain one or two carbon-carbon double        bonds and in which one or two of the ring carbons may optionally        be replaced by an oxygen or sulfur atom;    -   R₃ is methyl or ethyl;    -   R₄ is hydrogen, C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, C₁-C₄        alkoxy, trifluoromethoxy, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃,        —CH₂OF₃, CF₃, amino, nitro, —NH(C₁-C₄ alkyl), —N(CH₃)₂,        —NHCOCH₃, —NHCONHCH₃, —SO_(n)(C₁-C₄ alkyl) wherein n is 0, 1 or        2, cyano, hydroxy, —CO(C₁-C₄ alkyl), —CHO, cyano or —COO(C₁-C₄        alkyl) wherein said C₁-C₄ alkyl may optionally contain one        double or triple bond and may optionally be substituted with one        substituent selected from hydroxy, amino, —NHCOCH₃, —NH(C₁-C₂        alkyl), —N(C₁-C₂ alkyl)₂, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        C₁-C₃ alkoxy, C₁-C₃ thioalkyl, fluoro, chloro, cyano and nitro;    -   R₅ is phenyl or pyridyl, and R₅ is substituted with from one to        three substituents independently selected from fluoro, chloro,        C₁-C₆ alkyl, and C₁-C₆ alkoxy, or with one substituent selected        from hydroxy, iodo, bromo, formyl, cyano, nitro,        trifluoromethyl, amino, —(C₁-C₆ alkyl)O(C₁-C₆)alkyl, —NHCH₃,        —N(CH₃)₂, —COOH, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO₂NH₂,        —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), and        wherein the C₁-C₄ alkyl and C₁-C₆ alkyl moieties of the        foregoing R₅ groups may optionally be substituted with one or        two fluoro groups or with one substituent selected from hydroxy,        amino, methylamino, dimethylamino and acetyl; and    -   R₇ is hydrogen or methyl;    -   or a pharmaceutically acceptable salt of such compound;    -   comprising reacting a compound of the formula    -   wherein R₁₉ is methyl or ethyl, D is chloro and A, Z, R₄ and R₅        are defined as above, with a compound of the formula BH, wherein        B is defined as above, in the presence of a base; and then        optionally converting the compound of formula I formed in such        reaction into a pharmaceutically acceptable salt.

This invention also relates to a process for preparing a compound of theformula

or a pharmaceutically acceptable salt thereof, wherein

-   -   A is —CR₇ or N;    -   B is —NR₁R₂, —CR₁R₂R₁₁, —C(═CR₂R₁₂)R₁, —NHCHR₁R₂, —OCHR₁R₂,        —SCHR₁R₂, —CHR₂OR₁₂, —CHR₂SR₁₂, —C(S)R₂ or —C(O)R₂;    -   Z is NH, O, S, —N(C₁-C₂ alkyl) or —C(R₁₃R₁₄), wherein R₁₃ and        R₁₄ are each, independently, hydrogen, trifluoromethyl or        methyl, or one of R₁₃ and R₁₄ is cyano and the other is hydrogen        or methyl;    -   R₁ is C₁-C₆ alkyl which may optionally be substituted with one        or two substituents R₈ independently selected from the group        consisting of hydroxy, fluoro, chloro, bromo, iodo, CF₃ and        C₁-C₄ alkoxy, and wherein said C₁-C₆ alkyl and the (C₁-C₄)alkyl        moiety of said C₁-C₄ alkoxy may optionally contain one        carbon-carbon double or triple bond;    -   R₂ is C₁-C₁₂ alkyl, aryl or —(C₁-C₄ alkylene)aryl wherein said        aryl is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,        quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl,        benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl,        benzisoxazolyl, benzimidazolyl, indolyl, or benzoxazolyl; 3- to        8-membered cycloalkyl or —(C₁-C₆ alkylene)cycloalkyl, wherein        one or two of the ring carbons of said cycloalkyl having at        least 4 ring members and the cycloalkyl moiety of said —(C₁-C₆        alkylene)cycloalkyl having at least 4 ring members may        optionally be replaced by an oxygen or sulfur atom or by N-R₉        wherein R₉ is hydrogen or C₁-C₄ alkyl; and wherein each of the        foregoing R₂ groups may optionally be substituted with from one        to three substituents independently selected from chloro, fluoro        and C₁-C₄ alkyl, or with one substituent selected from bromo,        iodo, C₁-C₆ alkoxy, —O—CO—(C₁-C₆ alkyl), —O—CO—N(C₁-C₄        alkyl)(C₁-C₂ alkyl), —S(C₁-C₆ alkyl), CN, NO₂, —SO(C₁-C₄ alkyl),        and —SO₂(C₁-C₄ alkyl), and wherein said C₁-C₁₂ alkyl and the        C₁-C₄ alkylene moiety of said C₁-C₄ alkylene)aryl may optionally        contain one carbon-carbon double or triple bond;    -   or —NR₁R₂ may form a saturated 5- to 8-membered carbocyclic ring        which may optionally contain one or two carbon-carbon double        bonds and in which one or two of the ring carbons may optionally        be replaced by an oxygen or sulfur atom;    -   R₃ is methyl, ethyl, fluoro, chloro, bromo, iodo, cyano,        methoxy, OCF₃, methylthio, methylsulfonyl, CH₂OH, or CH₂OCH₃;    -   R₄ is hydrogen, C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, C₁-C₄        alkoxy, trifluoromethoxy, —CH₂OCH₃, —CH₂OCH₂CH₃, CH₂CH₂OCH₃,        —CH₂OF₃, CF₃, amino, nitro, —NH(C₁-C₄ alkyl), —N(CH₃)₂,        —NHCOCH₃, —NHCONHCH₃, —SO_(n)(C₁-C₄ alkyl) wherein n is 0, 1 or        2, cyano, hydroxy, —CO(C₁-C₄ alkyl), —CHO, cyano or —COO(C₁-C₄        alkyl) wherein said C₁-C₄ alkyl may optionally contain one        double or triple bond and may optionally be substituted with one        substituent selected from hydroxy, amino, —NHCOCH₃, —NH(C₁-C₂        alkyl), —N(C₁-C₂ alkyl)₂, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        C₁-C₃ alkoxy, C₁-C₃ thioalkyl, fluoro, chloro, cyano and nitro;    -   R₅ is phenyl or pyridyl and R₅ is substituted with from one to        three substituents independently selected from fluoro, chloro,        C₁-C₆ alkyl, and C₁-C₆ alkoxy, or with one substituent selected        from hydroxy, iodo, bromo, formyl, cyano, nitro,        trifluoromethyl, amino, —(C₁-C₆ alkyl)O(C₁-C₆)alkyl, —NHCH₃,        —N(CH₃)₂, —COOH, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO₂NH₂,        —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), and        wherein the C₁-C₄ alkyl and C₁-C₆ alkyl moieties of the        foregoing R₅ groups may optionally be substituted or two fluoro        groups or with one substituent selected from hydroxy, amino,        methylamino, dimethylamino and acetyl; and    -   R₇ is hydrogen or methyl;    -   with the proviso that when A is CH or CCH₃, then R₄ is an        electron deficient group such as NO₂, —COO(C₁-C₄)alkyl,        —C(═O)CH₃, —COOH or CN;

or a pharmaceutically acceptable salt of such compound;

comprising reacting a compound of the formula

wherein R₁₉ is methyl or ethyl and A is N, CH or CCH₃; and wherein whenA is N, then B″ and R₄ are defined, respectively, as B and R₄ aredefined in claim 1, and when A is CH or CH₃, then B″ is —NR₁R₂, —NHR₁R₂,—OCHR₁R₂ or cyano and R₄ is an electron deficient group such as NO₂,—COO(C₁-C₄ alkyl), —C(═O)CH₃, —COOH or CN;

-   -   with a compound of the formula R₅ZH, wherein R₅ and Z are        defined as above, and then optionally converting the compound of        formula I formed by such reaction into a pharmaceutically        acceptable salt.

This invention also relates to a process for preparing a compound of theformula

-   -   a wherein R₁₉ is methyl or ethyl;    -   D is chloro;    -   A is —CR₇ or N;    -   Z is NH, O, S, —N(C₁-C₂ alkyl) or —C(R₁₃R₁₄), wherein R₁₃ and        R₁₄ are each, independently, hydrogen, trifluoromethyl or        methyl, or one of R₁₃ and R₁₄ is cyano and the other is hydrogen        or methyl;    -   R₄ is hydrogen, C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, C₁-C₄        alkoxy, trifluoromethoxy, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃,        —CH₂OF₃, CF₃, amino, nitro, —NH(C₁-C₄ alkyl), —N(CH₃)₂,        —NHCOCH₃, —NHCONHCH₃, —SO_(n)(C₁-C₄ alkyl) wherein n is 0, 1 or        2, cyano, hydroxy, —CO(C₁-C₄ alkyl), —CHO, cyano or —COO(C₁-C₄        alkyl) wherein said C₁-C₄ alkyl may optionally contain one        double or triple bond and may optionally be substituted with one        substituent selected from hydroxy, amino, —NHCOCH₃, —NH(C₁-C₂        alkyl), —N(C₁-C₂ alkyl)₂, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        C₁-C₃ alkoxy, C₁-C₃ thioalkyl, fluoro, chloro, cyano and nitro;        and    -   R₅ is phenyl or pyridyl, and R₅ is substituted with from one to        three substituents independently selected from fluoro, chloro,        C₁-C₆ alkyl, and C₁-C₆ alkoxy, or with one substituent selected        from hydroxy, iodo, bromo, formyl, cyano, nitro,        trifluoromethyl, amino, C₁-C₆ alkyl)O(C₁-C₆)alkyl, —NHCH₃,        —N(CH₃)₂, —COOH, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO₂NH₂,        —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), and        wherein the C₁-C₄ alkyl and C₁-C₆ alkyl moieties of the        foregoing R₅ groups may optionally be substituted with one or        two fluoro groups or with one substituent selected from hydroxy,        amino, methylamino, dimethylamino and acetyl;    -   comprising reacting a compound of the formula    -   wherein R₁₉, R₄ and R₅ are defined as above and R₇ is hydrogen,        methyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, —O(C₁-C₄        alkyl), —C(O)(C₁-C₄ alkyl), —C(O)O(C₁-C₄ alkyl), —OCF₃, CF₃,        —CH₂OH, —CH₂OCH₃ or —CH₂OCH₂CH₃, with phorphorus trichloride.

This invention also relates to a process for preparing a compound of theformula

-   -   wherein R₁₉ is methyl or ethyl;    -   A is —CR₇ or N;    -   Z is O, S, or —C(R₁₃R₁₄), wherein R₁₃ and R₁₄ are each,        independently, hydrogen, trifluoromethyl or methyl, or one of        R₁₃ and R₁₄ is cyano and the other is hydrogen or methyl;    -   R₄ is hydrogen, C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, C₁-C₄        alkoxy, trifluoromethoxy, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃,        —CH₂OF₃, CF₃, amino, nitro, —NH(C₁-C₄ alkyl), —N(CH₃)₂,        —NHCOCH₃, —NHCONHCH₃, —SO_(n)(C₁-C₄ alkyl) wherein n is 0, 1 or        2, cyano, hydroxy, —CO(C₁-C₄ alkyl), —CHO, cyano or —COO(C₁-C₄        alkyl) wherein said C₁-C₄ alkyl may optionally contain one        double or triple bond and may optionally be substituted with one        substituent selected from hydroxy, amino, —NHCOCH₃, —NH(C₁-C₂        alkyl), —N(C₁-C₂ alkyl)₂, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        C₁-C₃ alkoxy, C₁-C₃ thioalkyl, fluoro, chloro, cyano and nitro;        and    -   R₅ is phenyl or pyridyl, and R₅ is substituted with from one to        three substituents independently selected from fluoro, chloro,        C₁-C₆ alkyl, and C₁-C₆ alkoxy, or with one substituent selected        from hydroxy, iodo, bromo, formyl, cyano, nitro,        trifluoromethyl, amino, —(C₁-C₆ alkyl)O(C₁-C₆)alkyl, —NHCH₃,        —N(CH₃)₂, —COOH, —COO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),        —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO₂NH₂,        —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), and        wherein the C₁-C₄ alkyl and C₁-C₆ alkyl moieties of the        foregoing R₅ groups may optionally be substituted with one or        two fluoro groups or with one substituent selected from hydroxy,        amino, methylamino, dimethylamino and acetyl;    -   comprising reacting a compound of the formula    -   wherein R₄, R₇ and R₁₉ are defined as above, with a compound of        the formula R₅OH or R₅SH, wherein R₅ is defined as above, in the        presence of a base.

DETAILED DESCRIPTION OF THE INVENTION

Methods of preparing the compounds and compositions of this inventionare described below. In the discussion and reaction schemes that follow,R₁ through R₉, R₁₁, R₁₂, R₁₆, R₁₇, R₁₉, A, B, G, the dashed lines andstructural formulae I, II, III, X, XI, XII and IV, unless otherwiseindicated, are defined as above.

Whenever reference is made herein to alkyl, both straight and branchedchain alkyl groups are encompassed. For example, “C₁-C₆ alkyl”encompasses both straight and branched chain alkyl groups of one to sixcarbon atoms, including (but not limited to) methyl, ethyl, isopropyl,t-butyl and hexyl.

Whenever R₂ or R₅ is a heterocyclic group, attachment of the group isthrough a carbon atom.

Whenever reference is made herein to C₁-C₄ alkyl or C₁-C₆ alkyl which“may contain one double or triple bond” in the above definitions, it isunderstood that at least two carbons are present in the alkyl for onedouble or triple bond.

Whenever reference is made herein to halo or halogen; fluoro, chloro,bromo or iodo is meant unless indicated otherwise.

The terms “treatment”, “treating”, and the like, are meant to includeboth slowing or reversing the progression of a disorder, as well ascuring the disorder. These terms also include alleviating or reducingthe symptoms of a disorder or condition, even if the disorder orcondition is not actually eliminated and even if progression of thedisorder or condition is not itself slowed or reversed. The term“treatment” and like terms also include prophylactic treatment ofdisorders and conditions.

The term “haloalkyl” refers to an alkyl group substituted by one or morehalogen atoms, i.e. one or more fluoro, bromo, iodo, or chloro atoms.Moreover, it is understood that when an alkyl group can be, according tothis specification and claims, substituted with, e.g., one to nine,e.g., nine atoms, that the optional one to nine fluorine atoms are onlyan option when a sufficient number of carbon atoms is present in thealkyl group.

The term “aryl” in the definitions above means, unless otherwiseindicated, an organic radical derived from an aromatic hydrocarbon byremoval of one hydrogen atom, which aromatic hydrocarbon. Examples ofaryl groups are phenyl and naphthyl.

The term “heterocycloalkyl”, unless otherwise specified means a 4 to 8membered mono-carbocyclic ring or bicyclic ring, wherein at least onecarbon atom is replaced with a hetero member selected from oxygen,nitrogen, N-(alkyl), or S(O)_(m), wherein m is zero, 1, 2, or 3.Generally, heterocycloalkyl groups comprise up to four hetero members,preferably 1, 2, or 3 hetero members. Heterocycloalkyl groups of thecompounds of the invention can contain optionally from one to threedouble bonds. The term “heterocycloalkyl” also includes heteroarylgroups. Examples of heteroaryl groups include thienyl, benzothienyl,pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl,benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl,benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl. Otherexamples of aryl groups are pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl,oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. Preferred heteroaryl groups arethiazolyl, thienyl, benzothienyl, pyridyl, quinolyl, quinazolinyl,quinoxalinyl, pyrazinyl, pyrimidinyl, indazolyl, imidazolyl, furanyl,benzimidazolyl, benzofuranyl, benzothiazolyl, benzisoxazolyl,isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl,benzoxazolyl, and benzothiadiazolyl. Other preferred heterocycloalkylgroups are tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino,piperidino, piperazino, [2,2,1]-azabicyclic rings, [2,2,2]-azabicyclicrings, [3,3,1]azabicyclic rings, quinuclidino, azetidino, azetidinono,oxindolo, dihydroimidazolo, and pyrrolidinono. Heterocyclolalkyl groupsin the compounds of the invention may be C-attached or N-attached wheresuch is possible.

Compounds of the formula I wherein B is —NR₁R₂, —NHCHR₁R₂, —OCHR₁R₂ or—SCHR₁R₂, and R₃ is methyl, ethyl or chloro (hereinafter R₁₉) may beprepared by reaction of a compound of the formula IV wherein D is Cl,and A, R₄, R₅, and Z are as defined above with reference to formula I,with a compound of the formula BH wherein B is as defined immediatelyabove. The reaction is carried out in a solvent in the presence of abase at a temperature of between about 0° to about 230° C. Suitablesolvents are organic solvents such as tetrahydrofuran (THF),acetonitrile, dimethylsulfoxide (DMSO), acetone, C₂-C₁₅ alkyl alcohol,chloroform (CHCl₃), benzene, xylene, toluene, sulfolane, pyridine,quinoline, 2,4,6-trimethylpyridine, acetamide, di-(C₁-C₂) alkylacetamideor 1-methyl-2-pyrrolidinone.

A preferred method of preparing compounds of the formula I wherein A is—CR₇ and B is —NR₁R₂ or —NHCHR₁R₂ is the two step procedure describedbelow. First, a compound of the formula IV is reacted with an excess ofR₁NH₂ or NH₃ or an equivalent NH₃ precursor (e.g., NaN₃, nBu₄N⁺N₃— orNH₂OH) at temperature from about 75° C. to about 250° C. and at apressure from about 0 to about 300 psi, in an appropriate solvent, asdescribed above, to form a compound of the formula I wherein B is —NHR₁,—NH₂, —NH₂OH or —N₃. Compounds of the formula I wherein B is —N₃ or—NH₂OH can be converted into the corresponding compounds of formula Iwherein B is —NH₂ by methods well known in the art such as hydrogenationor reduction. Alkylation of a compound of the formula I wherein B is—NHR, or —NH₂ with an appropriate alkyl halide in the presence of anappropriate base such as lithium or sodium bistrimethylsilylamide,lithium or sodium diisopropylamide, n-butyllithium or potassiumt-butoxide, in an appropriate solvent such as THF, dioxane or methylenechloride, will yield the corresponding compound of formula I wherein Bis —NR₁R₂. Alternatively, reductive amination of a compound of theformula I wherein B is —NHR₁ or —NH₂, for example, acylation, followedby reduction with a borohydride (eg., sodium borohydride) will form thecorresponding compound of formula I wherein B is —NR₁R₂ or NHCHR₁R₂.

When B is —NR₁R₂ or —NHCHR₁R₂, an excess of BH may be used both as areagent and as a base. Bases other than BH such as potassium carbonate,tri-(C₁-C₆)alkylamine or sodium hydride may also be used. The reactionis carried out at a temperature of about 75° to 230° C. When thereaction is carried out in the presence of a base, such as sodiumhydride, potassium C₁-C₄ alkoxide, or an organolithium compound such asn-butyllithium, a molar equivalent of the amine is used.

When B is —OCHR₁R₂ or —SCHR₁R₂, a base which is capable of deprotonatingBH may be used, such as an alkali metal hydride such as sodium orpotassium hydride, or an organometallic base such as sodiumdiisopropylamide, sodium bis(trimethylsilyl)amide, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, sodium or potassiumC₁-C₄ alkoxide, or n-butyllithium. The solvent used can be, for example,tetrahydrofuran, acetonitrile, dimethylsulfoxide, acetone, methylenechloride, toluene, a C₂-C₅ alcohol, chloroform, benzene, xylene, or1-methyl-2-pyrrolidinone, and the reaction temperature can range fromabout 0° C. to about 180° C., and is preferably from about 50° C. toabout 80° C.

Compounds of the formulae I, II and III wherein B is as defined withreference to formulae I, II and III and R₃ is defined with reference tothe same except that R₃ is not methyl or ethyl (hereinafter R₂₀, whichis defined as R₃ with the exception that it can not be methyl or ethyl)may be prepared by reacting a compound of the formulae I, II or IIIwherein R₃ is chloro with a nucleophile of the formula R₂₀H with orwithout an organic or inorganic base. Suitable bases include sodium andsodium hydride, when R₂₀H is an alkanol or an alkane thiol; and weakerbases such as potassium carbonate or triethylamine when R₂₀H is anamine. The compounds of formula I wherein R₂₀ is fluoro may be preparedfrom the corresponding compounds wherein R₂₀ is chloro on reaction withtetrabutylammonium fluoride. Suitable solvents are dimethylsulfoxide,tetrahydrofuran, or methylene chloride, preferably tetrahydrofuran.

Compounds of the formula I wherein B is —CR₁R₂R₁₁, —C(C═CR₂R₁₂)R₁,—CHR₂OR₁₂, —CHR₂SR₁₂, or —C(O)R₂, and R₃ is R₁₉, as defined above, maybe prepared as depicted in Scheme 1.

Compounds of the formula IV wherein D is cyano and A, R₄, R₅, and R₁₉are as defined above having formula IVA (not shown), prepared byreacting the corresponding compound wherein D is chloro with potassiumcyanide or copper cyanide in dimethylsulfoxide,1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF) or acetamide, arereacted with a Grignard reagent containing group R₂, as defined above,to form the compounds of formula IA. Further reaction of the compound offormula IA with a Grignard reagent containing R₁ as defined aboveprovides the compound of formula IB. Corresponding compounds of formulaIC wherein B″ is —CR₁R₂R₁₁, or —C(C═CR₂R₁₂)R₁ may be prepared byconventional methods. Thus, reaction of IB with an acid, such asconcentrated sulfuric acid in acetic acid, or Burgess inner salt, suchas (carboxysulfamoyl)triethylammonium hydroxide methyl ester, gives acompound of formula IC wherein B′ is —C(═CR₂R₁₂)R₁. Hydrogenation of acompound wherein B′ is —C(═CR₂R₁₂)R₁ using a palladium/carbon (Pd/C) orplatinum dioxide catalyst gives a compound IC wherein B′ is CHR₁R₂.Reaction of compound IB with diethylaminosulfur trifluoride ortriphenylphosphine/carbontetrachloride affords a compound IC wherein B′is —CR₁R₂F or —CR₁R₂Cl, respectively. Reduction of a compound of formulaIA with sodium borohydride gives a compound I wherein B is —CHR₂OH.Alkylation of this —CHR₂OH group with alkyl halide such as alkyl iodidein the presence of a base such as sodium hydride at room temperatureaffords a compound of formula I wherein B is —CHR₂OR₁₂.

Compounds of the formula II wherein R₃ is R₁₉ as defined above may beprepared from compounds of the formula IV wherein R₁₉, R₄, R₅ and A areas defined before, D is chloro, and YR₂₁ is NH or —CHR₂₁ wherein R₂₁ iscyano or —COO(C₁-C₄ alkyl), hereafter formula IVB, as shown in Scheme 2.

Compounds of the formula VII wherein R₄ and R₆ are each hydrogen and Yis N may be prepared by heating compounds of formula IVB with an acidcatalyst in a suitable solvent such as toluene, benzene, t-butanol,acetonitrile and acetone, preferably toluene. The acid catalyst may besulfuric acid, hydrochloric acid, p-toluene sulfonic acid, ormethylsulfonic acid, preferably p-toluene sulfonic acid.

When Y in formula IVB is CH or N, a base may be used to deprotonate theproton of the compound of formula IVB. Suitable solvents aretetrahydrofuran, toluene, and methylene chloride, suitable reactiontemperatures are between about −78° C. and 100° C., preferably −78° to50° C., and suitable bases are sodium hydride, potassium hydride,potassium t-butoxide, lithium bis(trimethylsilyl) amide, and lithium orsodium diisopropylamide.

Compounds of the formula VII wherein R₄ and R₆ are each hydrogen may bedeprotonated with a base such as sodium hydride, or an organometalliccompound such as lithium bis(trimethylsilyl)amide followed by quenchingwith an electrophile compound containing the group R₄, such as R₄Lwherein L is a leaving group such as iodo, bromo, mesylate, tosylate orwith p-tolyl-N-fluoro-N-C₁-C₆ alkyl sulfonamide, iodine, p-nitrobenzene,dimethylformamide, di(C₁-C₄ alkyl)ketone, formaldehyde, (C₁-C₄ alkyl)aldehyde or bromine, to provide a compound of formula VII wherein R₄ isfluoro, chloro, bromo, iodo, hydroxy, C₁-C₄ alkyl, S(C₁-C₄ alkyl), CHO,CH(OH)(C₁-C₄ alkyl), C(OH)(di-C₁-C₄ alkyl) or CH₂OH. Furtherconventional alkylation of the hydroxy group or oxidation of thethioalkyl group leads to compounds of formula VII wherein R₄ is C₁-C₄alkoxy and SO_(n)(C₁-C₄ alkyl) wherein n is 1 or 2, respectively.Oxidation of compounds of formula VII wherein R₄ is hydroxy and R₆ ishydrogen affords corresponding compounds wherein CR₄R₆ is C═O, which onreductive amination with an appropriate amine convert into correspondingcompounds wherein R₄ is amino. The compounds of formula VII wherein R₄is nitro or amino may be formed by reacting compounds of formula VIIwherein R₄ and R₆ are both hydrogen with alkyl nitrite to form compoundswherein CR₄R₆ is C═NOH and oxidizing or reducing to give the compoundsof formula VII wherein R₄ is nitro or amine, respectively.

Compounds of the formula VII, when one of R₄ and R₆ is hydrogen, may beconverted into corresponding compounds wherein R₁₆ and R₁₇ are bothhydrogen by reduction with a reducing agent such as lithium aluminumhydride in tetrahydrofuran. The same reduction leads to compoundswherein R₁₆ is hydrogen and R₁₇ is hydroxy, when both of R₄ and R₆ arenot hydrogen. Alkylation of R₁₇ is hydroxy with C₁-C₄ alkyl iodide inthe presence of sodium hydride gives the corresponding compound whereinR₁₇ is O(C₁-C₄ alkyl). Reaction of compounds of formula VII with anorganometallic compound such as di(C₁-C₆ alkyl)zinc, C₁-C₆ alkyllithium, or C₁-C₆ alkyl magnesiumbromide affords compounds of formulaVIII wherein one of R₁₆ or R₁₇ is C₁-C₆ alkyl and the other is hydroxy.

The conversion of compounds of formula VIII to corresponding compoundsof formula IIA is by the methods described above for preparation ofcompounds of formula I.

The compounds of formula III wherein G is oxygen or sulfur and R₆ ishydrogen may be prepared by reacting compounds of formula I wherein R₄is amino and Z is NH with phosgene, diphosgene, triphosgene orthiophosgene. The reaction is in the presence of a base such astri(C₁-C₄ alkyl)amine in a suitable solvent, preferable tetrahydrofuraneat about −78° to about 50° C., preferably at 0° C. to room temperature.Standard alkylation of these compounds wherein R₆ is hydrogen with asuitable base such as sodium hydride in a suitable solvent such as drytetrahydrofuran provides compounds of the formula III wherein R₆ isC₁-C₄ alkyl.

Compounds of the formula III wherein G is alkyl may be prepared byreacting a compound of the formula I wherein R₄ is amino and Z is NHwith a compound of the formula GC(OC₁-C₂ alkyl)₃ in the presence of anacid such as p-toluenesulfonic acid (p-TsOH), methanesulfonic acid(MsOH), hydrogen chloride gas (HCl_(g)) or concentrated sulfuric acid(H₂SO₄) in an appropriate sovlent such as toluene, xylene, benzene,dioxane or THF at a tempeature from about room temperature to about 140°C., preferably from about 50° C. to about the reflux temperature.Alternatively, a compound of the formula I wherein R₄ is amino and Z isNH can be reacted with [G(C═O)]₂O, G(C═O)Cl or G(C═O)F in the presenceof a base such as pyridine, a derivative of pyridine or atri-(C₁-C₄)alkylamine, in an appropriate solvent such as CH₂Cl₂, CHCl₃,THF, dioxane, toluene or benzene, at a temperature from about 0° C. toabout the reflux temperature of the reaction mixture, preferably fromabout 0° C. to about room temperature, followed by ring cyclizationunder acidic conditions (e g, with pTSOH, MSOH, HCl_(g), hydrogenbromide gas (HBr_(g)) or concentrated H₂SO₄). The ring cydization can becarried out in an appropriate solvent such as a C₁-C₅ alcohol, toluene,xylene, benzene, dioxane or THF. Suitable temperatures for this reactioncan range from about room temperature to about 140° C. Preferably, thereaction temperature is between about 50° C. and about the refluxtemperature.

Compounds of the formula III wherein G is —O—(C₁-C₂ alkyl) or —OCF₃ maybe prepared by reacting a compound of the formula III wherein G isoxygen and R₆ is hydrogen with a compound of the formula GOSO₂CF₃ in thepresence of a base such as tri(C₁-C₄ alkyl)amine, or with lithiumbistrimethylsilylamide in HMPA or DMF, and then quenching the reactionwith a compound of the formula GOSO₂OG or G-X wherein X is bromo, chloroor SO₃CF₃.

The compounds of formula IV wherein D is chloro and ZR₅ is NHR₅ may beprepared from compounds of formula V:

-   -   wherein A and R₄ are as defined with reference to formula I and        R₁₉ is as defined above, by reaction with R₅NH₂. The reaction is        in tetrahydrofuran or dimethylsulfoxide at about 0° C. to about        150° C., preferably 50° to 130° C. The compounds of formula IV        wherein D is chloro and Z is O, S, CHR₂₁ wherein R₂₁ is an        electron deficient group such as cyano, C(═O)R, COOR, wherein R        is C₁-C₄ alkyl, benzoyl or allyl, or SO_(n)— phenyl wherein n=0,        1 or 2 may be prepared by reacting compounds of formula V with        R₅OH, R₅SH, R₅NH₂ or R₅CHR₂₁. The reaction proceeds in the        presence of a base which is capable of deprotonating R₅ZH, such        as sodium hydride, potassium hydride, potassium carbonate,        lithium or sodium bis(trimethylsilyl)amide, lithium or sodium        dialkylamide, sodium or potassium (C₁-C₄ alkoxide) or        n-butyllithium, with or without other organometal halides such        as copper (I) bromide, iodide or chloride, copper (II) oxide,        copper (I) oxide, copper metal and trialkyltinchloride. Examples        of solvents that may be used are tetrahydrofuran,        dimethylsulfoxide, acetonitrile, methylene chloride,        1-methyl-2-pyrrolidinone, pyridine, quinoline,        N,N-dialkylacetamides, 2,4,6-trimethylpyridine,        N,N-dialkylformamides, eg., N,N-dimethylformamide (DMF),        hexamethyl phosphoramide and toluene. The reaction temperature        may range from about 0° C. to about 180° C., and is preferably        from about 0° to about 150° C.

Compounds of the formula IV wherein A is CR₇, D is chloro and Z is O, S,CHR₂, may be prepared by reduction of compounds of formula X, depictedbelow, wherein R₇ and Z are as defined immediately above, with areducing agent such as phosphorous trichloride in an appropriate solventsuch as methylene chloride or chloroform at temperature from about 0° C.to about 100° C., preferably from about room temperature to about thereflux temperature of the solvent.

Compounds of the formula X may be prepared from compounds of the formulaXI, depicted above, wherein R₄ is as defined as it is for formula I andR₁₉ is as defined above (i.e., methyl or ethyl), by reaction with acompound of the formula R₅OH, R₅SH or R₅CHR₂₁. This reaction proceeds inthe presence of a base which is capable of deprotonating R₅ZH, such assodium hydride, potassium hydride, lithium, sodium or potassiumbis(trimethylsilyl)amide, lithium, sodium or potassium dialkylamide,sodium or potassium C₁-C₄alkoxide, or n-butyllithium. Suitable solventsinclude tetrahydrofuran, dioxane, dimethylsulfoxide,1-methyl-2-pyrrolidinone, pyridine, N,N-di-C₁-C₄ alkyl)acetamides,acetamide, N,N-di-(C₁-C₄ alkyl)formamides, acetonitrile, methylenechloride, touluene and xylene. Suitable reaction temperatures may rangefrom about - 78° C. to about 150° C., and are preferably between about40° C. to about 150° C.

Compounds of the formula XI may be prepared by reacting thecorresponding compounds of formula V wherein A is —CR₇ and R₄ and R₁₉are defined as above, with an oxidizing agent such as m-chloroperbenzoicacid, peracetic acid or pertrifluoroacetic acid, in a solvent such asmethylene chloride, chloroform, acetic acid, DMF, methanol or a mixtureof one or more of the foregoing solvents, at temperature from about 0°C. to about 100° C., preferably from about room temperature to about 60°C.

When R₄ is an electron withdrawing group such as a NO₂, —COO(C₁-C₄alkyl), —COOH, CN or —CO(C₁-C₄)alkyl, the reaction order for thecoupling reactions that introduce the B and ZR₅ groups in the synthesisof compounds of formula I may be reversed. The B group may be introducedbefore the ZR₅ coupling step using the methods analogous to thosedescribed above. For example, compounds of the formula I wherein R₄ isan election deficient group may be prepared by reacting a compound ofthe formula XII with a compound of the formula HZR₅. Compounds of theformula XII may be prepared by reacting a compound of the formula Vwherein A is CR₇ and R₁₉ and R₄ are defined as above with a compound ofthe formula B″H in the presence of a base.

Compounds of the formula IV wherein D is chloro and Z is —N(C₁-C₄ alkyl)may be prepared by reacting the corresponding compounds wherein Z is NHwith a base, at a temperature from about −78° C. to about 100° C.,preferably from about 0° C. to about room temperature, followed byquenching with C₁-C₄ alkyl iodide or bromide. Suitable bases include,for example, sodium hydride, lithium or sodium bis(trimethylsilyl)amide,lithium or sodium dialkylamide, and n-butyllithium. Suitable solventsinclude, for example, tetrahydrofuran, dimethylsulfoxide, toluene,benzene or methylene chloride.

Compounds of the formula IV wherein D is chloro, hydroxy or OP wherein Pis a standard protecting group for hydroxy and Z is —CR₁₃R₁₄ may beprepared by alkylation, using an R₁₃ containing alkylating agent such asR₁₃I, compounds of the formula IV wherein Z is —CHR₂₁ in the presence ofa base that is capable of deprotonating the proton in the Z group, asmentioned above, followed by quenching with an R₁₄ containing alkylatingagent such as R₁₄I. Heating compounds of the formula IV wherein D ischloro or hydrogen and Z is —CH(CN) in about 85% phosphoric acid atabout the reflux temperature yields the corresponding compounds offormula IV wherein D is hydroxy and Z is CH₂. Deprotonation of thecompounds of formula IV wherein Z is CH₂ with a base, such as describedabove for deprotonation of R₅ZH, followed by quenching with a suitableelectrophile such as a (C₁-C₆ alkyl)iodide, iodine, bromine,acetylchloride, formaldehyde, acetone, p-tolyl-N-fluoro-N-(C₁-C₆alkyl)sulfonamide, nitrobenzene, C₁-C₆ alkylnitrite, ethylene oxide ordihaloethane yields the corresponding compounds of formula IV wherein Zis —CHR₁₃, —CH(OH), cyclopropyl or —C(NOH). Further alkylation ofcompounds wherein Z is —CHR₁₃, e.g., as described immediately above,with an alkylating agent of the formula R₁₄I, produces the correspondingcompounds wherein Z is —C(R₁₃R₁₄).

Conversion of —C(R₅)NOH or —CH(OH)R₅ to C(O)R₅ may be accomplished byknown methods. Hydrogenation or reduction of compounds wherein Z is—C═NOH provides compounds wherein Z is —CHNH₂. Some of the intermediatesmay require a protecting or deprotecting procedure to control thereaction selectivity using standard organic chemistry.

Compounds of the formula V wherein A is N (hereinafter referred to ascompounds of the formula VB) or A is CR₇ (i.e., compounds of the formulaVA), and R₄ and R₁₉ are defined as they are for formula I, may beprepared by reacting the corresponding compounds of formulae VIB andVIA, respectively, with 1 equivalent or an excess of POCl₃ at atemperature from about room temperature to about 180° C., preferably atthe reflux temperature, with or without a solvent. Compounds of formulaVIA may be prepared by the methods analogous to those described in theliterature and well known to those skilled in the art. (See Helv.Chimica Acta., 25, p. 1306-1313 (1942)).

Compounds of formula VIB may be prepared by reacting 1 equivalent of theHCl salt of R₁₉C(═NH)(NH₂), 1 equivalent of R₄CH(COO—(C₁-C₂ alkyl))₂,and 2 equivalents of a base such as a sodium alkoxide, e.g., sodiummethoxide in a mixture of an alcohol (e.g., methanol), and acetone at atemperature from about 50° C. to about 200° C., preferably at the refluxtemperature.

When compounds of this invention contain one or more chiral centers, itis understood that the invention includes the racemic mixtures as wellas all individual enantiomers and diastereomers of such compounds, andmixtures thereof.

The acid addition salts of compounds of the formulae I, II and III (“theactive compounds of this invention) can be prepared in a conventionalmanner by treating a solution or suspension of the corresponding freebase with one chemical equivalent of a pharmaceutically acceptable acid.Conventional concentration or crystallization techniques can be employedto isolate the salts. Illustrative of suitable acids are acetic, lactic,succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic,cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic,hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, and related acids.

The active compounds of this invention may be administered alone or incombination with pharmaceutically acceptable carriers, in either singleor multiple doses. Suitable pharmaceutical carriers include inert soliddiluents or fillers, sterile aqueous solutions and various organicsolvents. The pharmaceutical compositions formed by combining the novelcompounds of formulae I, II and III and their pharmaceuticallyacceptable carriers can then be readily administered in a variety ofdosage forms such as tablets, powders, lozenges, syrups, injectablesolutions and the like. These pharmaceutical compositions can, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus, for purposes of oral administration,tablets containing various excipients such as sodium citrate, calciumcarbonate and calcium phosphate may be employed along with variousdisintegrants such as starch, methylcellulose, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Preferred materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions containing an active compoundof this invention or a pharmaceutically acceptable salt thereof insesame or peanut oil, aqueous propylene glycol, or in sterile aqueoussolution may be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

The effective dosages for compounds of the formulae I, II or III andtheir salts will depend on the intended route of administration andfactors such as the age and weight of the patient, as generally known toa physician. The dosages will also depend on the particular illness tobe treated. For instance, the daily dosage for stress-induced illnesses,inflammatory disorders, Alzheimer's disease, gastrointestinal diseases,anorexia nervosa, hemorrhagic stress and drug and alcohol withdrawalsymptoms will generally range from about 0.1 to about 50 mg/kg bodyweight of the patient to be treated. The effective dose can bedetermined by those of ordinary skill in the art by reference to textspertaining to treatment of the particular disorder or condition to betreated.

Methods that may be used to determine the CRF antagonist acivity of theactive compounds of this invention and their pharmaceutically acceptablesalts are described in Endocrinology, 116, 1653-1659 (1985) andPeptides, 10, 179-188 (1985). The binding activities for compounds offormulae I, II and III, expressed as IC₅₀ values, generally range fromabout 0.5 nanomolar to about 10 micromolar.

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (¹H NMR) and C¹³ nuclearmagnetic resonance spectra (C¹³ NMR) were measured for solutions indeuterochloroform (CDCl₃) and peak positions are expressed in parts permillion (ppm) downfield from tetramethylsilane (TMS). The peak shapesare denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; b, broad.

The following abbreviations are used in the Examples: Ph=phenyl;iPr=isopropyl; HRMS=high resolution mass spectrum.

EXAMPLE 1 A. Butyl-(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-ethylamine

A mixture of 2,5-dimethyl-4,6-dichloro-pyrimidine (0.999 g, 5.64 mmol)in 5 ml of acetonitrile was treated with triethylamine (0.571 g, 5.65mmol) and N-butyl-ethyl-amine (0.570 g, 5.65 mmol) and heated at refluxovernight. The mixture was cooled, diluted with water and dilutehydrogen chloride, and extracted with ethyl acetate. The organic layerwas neutralized with saturated potassium carbonate, washed with brine,dried and concentrated to give 0.877 g (64%) of title compound as ayellow oil. ¹H NMR (CDCl₃) δ 0.90 (t, 3 H), 1.15 (t, 3 H), 1.22-1.36(m,2 H), 1.5-1.6(m, 2 H), 2.20 (s, 3 H), 2.45 (s, 3 H), 3.25-3.48 (m, 4 H)ppm.

B.N-Butyl-N-ethyl-2,5-dimethyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine

A mixture of butyl-(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-ethylamine(398 mg, 1.65 mmol), 2,4,6-trimethylaniline (4.04 g, 30 mmol) anddiisopropyl-ethyl-amine (200 mg, 1.55 mmol) was heated at 210 to 230° C.overnight. The mixture was quenched with water and dilute hydrogenchloride, and extracted with ethyl acetate. The organic layer wasneutralized with saturated potassium carbonate, washed with brine, driedand concentrated to give a dark oil. The oil was distilled to give 579mg of dark oil which was then purified through silica gel columnchromatography using 1:1 hexane to chloroform as eluent to give 327 mgof title compound as a yellow solid. ¹H NMR (CDCl₃) δ 0.92 (t, 3 H),1.14 (t, 3 H), 1.2-1.4 (m, 2 h), 1.45-1.60 (m, 2 H), 1.85 (s, 3 H), 2.16(s, 6 H), 2.30 (s, 3 H), 2.33 (s, 3 H), 3.2-3.4 (m, 4 H), 5.8 (brs, 1H), 6.90 (s, 2 H) ppm.

EXAMPLE 2 A. Butyl-(6-chloro-2-methyl-pyrimidin-4-yl)-ethylamine

A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10 mmol) in 5 mlof acetonitrile was treated with N-butyl-ethyl-amine (2.000 g, 20 mmol)and heated at reflux for 0.5 hours. The mixture was cooled, diluted withwater and extracted withethyl acetate. The organic layer was washed withbrine, dried and concentrated to give 2.271 g (100%) of title compoundas a light-brown oil. ¹H NMR (CDCl₃) δ 0.93 (t, 3 H), 1.13 (t, 3 H),1.22-1.36 (m, 2 H), 1.45-1.6 (m, 2 H), 2.43 (s, 3 H), 3.25-3.60 (m, 4H), 6.15 (s,1 H) ppm.

B.N-Butyl-N-ethyl-2-methyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine

A mixture of butyl-6-chloro-2-methyl-pyrimidin-4-yl)-ethylamine (1.006g, 4.42 mmol), and 2,4,6-trimethylaniline (3 ml) was heated at refluxovernight. The mixture was quenched with water and extracted with ethylacetate. The organic layer was dried and concentrated to give 2.862 g ofa brown oil. The oil was purified through silica gel columnchromatography to give 981 mg (68%) of title compound as a yellow oil.¹H NMR (CDCl₃) δ 0.80 (t, 3 H), 1.1-1.3 (m, 2 H), 1.3-1.5 (m, 2 H), 2.17(s, 6 H), 2.27 (s, 3 H), 2.41 (s, 3 H), 3.2 (m, 2 H), 3.36 (m, 2 H),4.66 (s, 1 H), 6.90 (s, 2 H) ppm.

EXAMPLE 3 A. Butyl-(6-chloro-2-methyl-5-ethyl-pyrimidin-4-yl)-ethylamine

A mixture of 2-methyl-5-ethyl-4,6-dichloro-pyrimidine (1.009 g, 5.28mmol) in 5 ml of acetonitrile was treated with triethylamine (0.571 g,5.65 mmol) and N-butyl-ethyl-amine (0.540 g, 5.31 mmol) and heated atreflux overnight. The mixture was diluted with water and dilute hydrogenchloride, and extracted with ethyl acetate. The organic layer wasneutralized with saturated potassium carbonate and washed with brine,dried and concentrated to give 1.193 g of yellow oil which was purifiedthrough silica gel column chromatography to give 1.157 g (86%) of titlecompound as a yellow oil. ¹H NMR (CDCl₃) δ 0.90 (t, 3 H), 1.13 (t, 3 H),1.18 (t, 3 H), 1.1-1.33 (m, 2 H), 1.4-1.6 (m, 2 h), 2.41 (s, 3 H), 2.62(q, 2 H), 3.25-3.48 (m, 4 H) ppm.

B.N-Butyl-N-ethyl-2-methyl-5-ethyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine

A mixture of butyl-(6-chloro-2-methyl-5-ethyl-pyrimidin-4-yl)-ethylamine(200 mg, 0.78 mmol) and 2,4,6-trimethylaniline (0.963 g, 7.1 mmol) washeated at reflux for 4 hours. The mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed withsaturated potassium carbonate and brine, dried and concentrated to givea dark oil. The oil was distilled to give 579 mg of the dark oil whichwas then purified through silica gel column chromatography usingchloroform as eluent to give the title compound as a brown oil. ¹H NMR(CDCl₃) δ 0.93 (t, 3 H), 1.14 (t, 3 H), 1.1-1.4 (m, 4 H), 1.45-1.60 (m,2 H), 2.17 (s, 6 H), 2.30 (s, 3 H), 2.33 (s, 3 H), 3.2-3.4 (m, 4 H),6.90 (s, 2 H) ppm.

EXAMPLE 42-Methyl-5-nitro-N,N′-bis-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine

A mixture of 2-methyl-5-nitro-4,6-dichloropyrimidine (0.513 g, 2.47mmol) in 6 ml of acetonitrile was treated with 2,4,6-trimethylaniline(0.333 g, 2.46 mmol) and triethylamine (1 ml) and stirred at roomtemperature for 4 hours. The mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed with brine,dried and concentrated to give 0.622 g of bright yellow solid. The solidwas purified through silica gel column chromatography to give(6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethylphenyl) amineand the title compound. ¹H NMR (CDCl₃) for6-(chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethylphenyl) amineδ 2.16 (s, 6 H), 2.33 (s, 3 H), 2.43 (s, 3 H), 6.95 (s, 2 H), 8.79 (s, 1H) ppm. ¹H NMR (CDCl₃) for2-methyl-5-nitro-N,N′-bis-2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine:δ 2.11 (s, 3 H), 2.22 (s, 12 H), 2.33 (s, 3 H), 6.96 (s, 4 H), 10.44 (s,2 H) ppm.

EXAMPLE 5N-Butyl-N-ethyl-2-methyl-5-nitro-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine

A mixture of6-(chloro-2-methyl-5-nitropyrimidin-4-yl-(2,4,6-trimethyl-phenyl)amine(838 mg, 2.10 mmol) and N-ethyl-n-butyl-amine (555 mg, 5.48 mmol) in 15ml acetonitrile was heated at reflux for 2 hours. The mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried and concentrated to give 0.837 g of yellowoil. The solid was purified through silica gel column chromatographyusing 1:1 hexane to chloroform as eluent to give 753 mg of the titlecompound as a yellow oil. ¹H NMR (CDCl₃) δ 0.95 (t, 3 H), 1.26 (t, 3 H),1.2-1.4 (m, 2 H), 1.55-1.75 (m, 2 H), 2.17 (s, 6 H), 2.23 (s, 3 H), 2.31(s, 3 H), 3.4-3.6 (m, 4 H), 6.93 (s, 2 H), 9.43 (s, 1 H) ppm.

EXAMPLE 6

The following compounds were prepared by a method analogous to that ofExamples 3 or 5 starting with an appropriate amine and appropriate(6-chloro-2-methyl-5-substituted-pyrimidin-4-yl)-(2,4,6-trimethylphenyl)amine.

N-Propyl-N-ethyl-2-methyl-5-nitro-N′-(2,4,6-trimethylphenyl)-pydmidine-4,6-diamine:¹H NMR (CDCl₃) δ 0.93 (t, 3 H), 1.26 (t, 3 H). 1.6-1.8 (m, 2 H), 2.17(s, 6 H), 2.23 (s, 3 H). 2.31 (s, 3 H), 3.4-3.55 (m, 4 H), 6.93 (s, 2H), 9.41 (s, 1 H) ppm.

N-Butyl-5-ethyl-2-methyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine:¹H NMR (CDCl₃) δ 0.98 (t, 3 H), 1.12 (t, 3 H), 1.3-1.5 (m, 2 H), 1.5-1.7(m, 2 H), 2.17 (s, 3 H), 2.30 (s, 3 H), 3.4-3.5 (m, 2 H), 4.30 (brs, 1H), 5.65 (brs, 1 H), 6.91 (s, 2 H) ppm.

5,N-Diethyl-2-methyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine:¹H NMR (CDCl₃) δ 1.09 (t, 3 H), 1.25 (t, 3 H), 2.17 (s, 3 H), 2.30 (s, 3H), 2.31 (s, 3 H), 3.4-3.6 (m, 2 H), 4.35 (brs, 1 H), 6.90 (s, 2 H) ppm.

EXAMPLE 7N-Butyl-N-ethyl-2-methyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,5,6-triamine

A mixture ofN-butyl-N-ethyl-2-methyl-5-nitro-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine(242 mg, 0.65 mmol) and platinum oxide (35 mg) in 50 ml ethanol washydrogenated at 40 psi for 24 hours. The mixture was filtered throughcelite and concentrated to dryness to give 217 mg of yellow oil. The oilwas purified through silica gel column chromatography to give 135 mg(61%) of title compound. ¹H NMR (CDCl₃) δ 0.91 (t, 3 H), 1.09 (t, 3 H),1.2-1.4 (m, 2 H), 1.4-1.6 (m, 2 H), 2.18 (s, 6 H), 2.30 (s, 3 H), 2.34(s, 3 H), 3.0 (brs, 2 H), 3.1-3.3 (m, 4 H), 5.89 (s, 1 H), 6.92 (s, 2 H)ppm.

EXAMPLE 8

The following compounds were prepared by the method of Example 7 byhydrogenation of the corresponding 5-nitro derivatives.

N-Propyl-N-ethyl-2-methyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,5,6-triamine:

¹H NMR (CDCl₃) δ 0.89 (t, 3 H), 1.09 (t, 3 H), 1.45-1.60 (m, 2 H), 2.18(s, 6 H), 2.30 (s, 3 H), 2.34 (s, 3 H), 3.80 (brs, 2 H), 3.1-3.30 (m, 4H), 5.95 (brs, 1 H), 6.92 (s, 2 H) ppm.

2-Methyl-N,N′-bis-(2,4,6-trimethylphenyl)-pyrimidine-4,5,6-triamine:

¹H NMR (CDCl₃) δ 2.04 (brs, 2 H), 2.21 (s, 12 H), 2.22 (s, 3 H), 2.30(s, 6 H), 6.30 (s, 2 H), 6.92 (s, 4 H) ppm.

EXAMPLE 96-(Ethyl-propyl-amino-2-methyl-9-(2,4,6-trimethylphenyl)-7,9-dihydropurin-8-one

A mixture ofN-propyl-N-ethyl-2-methyl-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5,6-triamine(120 mg, 0.35 mmol) and triethylamine (87 mg, 0.86 mmol) in 5 ml of drytetrahydrofuran was treated with triphosgene (41 mg, 0.14 mmol) at 0° C.Precipitate formed immediately and the reaction mixture was warmed toroom temperature. After stirring for 30 minutes the mixture wasfiltered. The filtrate was concentrated to dryness to give 125 mg (100%)of title compound of a greenish color. ¹H NMR (CDCl₃) δ 0.90 (t, 3 H),1.21 (t, 3 H), 1.65 (m, 2 H), 2.10 (s, 6 H), 2.34 (s, 3 H), 2.39 (s, 3H), 3.48 (dd, 2 H), 3.58 (q, 2 H), 6.99 (s, 2 H), 9.63 (s, 1 H) ppm.

EXAMPLE 106-(Ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihydropurin-8-one

A mixture of the title compound of Example 9 (54 mg, 0.15 mmol) in 3 mlof dry tetrahydrofuran was treated with sodium hydride (9 mg, 0.23 mmol,60% in oil) at room temperature. The mixture was then treated with 0.02ml of methyl iodide and stirred at room temperature overnight. Themixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried and concentrated to give 60 mg of brown oil. Theoil was purified through silica gel column chromatography usingchloroform as eluent to give 56 mg of the title compound as a yellow oilwhich crystallized on standing. ¹H NMR (CDCl₃) δ 0.92 (t, 3 H), 1.17 (t,3 H), 1.63 (m, 2 H), 2.06 (s, 6 H), 2.33 (s, 3 H), 2.46 (s, 3 H), 3.32(dd, 2 H), 3.40 (q, 2 H), 3.63 (s, 3 H), 7.00 (s, 2 H) ppm.

EXAMPLE 11

The following compounds were prepared by the method of Example 10 byreacting the title compound of Example 9 with an appropriate alkyliodide.

7-Ethyl-6-(ethyl-propyl-amino)-2-methyl-9-(2,4,6-trimethylphenyl)-7,9-dihydropurin)-8-one:

¹H NMR (CDCl₃) δ 0.92 (t, 3 H), 1.14 (t, 3 H), 1.23 (m, 3 H), 1.58 (m, 2H), 2.04 (s, 6 H), 2.31 (s, 3 H), 2.45 (s, 3 H), 3.32 (dd, 2 H), 3.36(q, 2 H), 4.08 (q, 2 H), 7.00 (s, 2 H) ppm.

6-(Ethyl-propyl-amino)-2-methyl-7-propyl-9-(2,4,6-trimethylphenyl)-7,9-dihydropurin-8-one:

¹H NMR (CDCl₃) δ 0.87 (t, 3 H), 0.90 (t, 3 H), 1.15 (t, 3 H), 1.5-12.8(m, 4 H), 2.05 (s, 6 H), 2.33 (s, 3 H), 2.47 (s, 3 H), 3.32 (dd, 2 H),3.38 (q, 2 H), 4.01 (q, 2 H), 7.00 (s, 2 H) ppm.

EXAMPLE 12[4-Chloro-2-methyl-6-(2,4,6-bimethylphenylamino)-pyrimidin-5-yl]-aceticacid ethyl ester

A mixture of (2-methyl-4,6-dichloro-pyrimidine-5-yl)-acetic acid ethylester (1.470 g, 5.9 mmol) and 2,4,6-trimethylaniline (2.56 ml, 17.7mmol), in 15 ml of dimethylsulfoxide was heated at 120° C. ovemight and138° C. for 5 hours. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried andconcentrated to give a brown oil. The oil was purified through silicagel column chromatography to give 1.070 g (52%) of the title compound asa tan solid. ¹H NMR (CDCl₃) δ 1.30 (t, 3 H), 2.14 (s, 6 H), 2.32 (s, 3H), 2.37 (s, 3 H), 3.79 (s, 2 H), 4.23 (q, 2 H), 7.00 (s, 2 H), 7.02 (s,1 H) ppm.

EXAMPLE 13

A.4-Chloro-2-methyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one

A mixture of the title compound of Example 12 (960 mg, 2.76 mmol) andp-toluene sulfonic acid (105 mg, 0.55 mmol) in 10 ml of toluene washeated at reflux under Dean-Stark trap for 8 hours. The mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried and concentrated to give 800 mg of a brownmass which was purified through silica gel column chromatography to give348 mg (42%) of the title compound as a yellow powder. ¹H NMR (CDCl₃) δ2.06 (s, 6 H), 2.34 (s, 3 H), 2.56 (s, 3 H), 3.75 (s, 2 H), 7.02 (s, 2H) ppm.

B.4-(1-Hydroxymethyl-propylamino)-2-methyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3d]pyrimidine-6-one

A mixture of the compound prepared under A (168 mg, 0.557 mmol) and(S)-2-amino-butanol (0.27 ml, 2.78 mmol) in 5 ml of dimethyl sulfoxidewas heated at 145° C. for 5 hours. The mixture was quenched with waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried and concentrated to give an oil. The oil was purifiedthrough silica gel column chromatography, followed by recrystallizationwith diethyl ether to give 166 mg of the title compound as a grey solid.

¹H NMR (CDCl₃) δ 1.25 (t, 6 H), 1.5-1.8 (m, 2 H), 2.07 (s, 6 H), 2.31(s, 3 H), 2.37 (s, 3 H), 3.50 (s, 2 H), 3.4-3.9 (m, 2 H), 4.0 (m, 1 H),4.* (d, 1 H), 7.00 (s, 2 H) ppm.

EXAMPLE 144-Diethylamino-2-methyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one

The title compound was prepared by the method of Example 13B withdiethylamine instead of (S)-2-amino-butanol. ¹H NMR (CDCl₃) δ 1.02 (t, 3H), 2.08 (s, 6 H), 2.31 (s, 3 H), 2.37 (s, 3 H), 3.55 (q, 4 H), 3.85 (s,2 H), 6.95 (s, 2 H) ppm.

EXAMPLE 15

A.4-Chloro-2,5,5-trimethyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrmidin-6-oneand4-Chloro-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one

A mixture of4-chloro-2-methyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one(93 mg, 0.31 mmol) and sodium hydride (14 mg, 0.34 mmol, 60% in oil) intetrahydrofuran (THF) was stirred for 5 minutes, then treated with anexcess of methyl iodide and stirred for 1 hour. The mixture was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with brine, dried and concentrated to give an oil. The oil waspurified through silica gel column chromatography to give 32 mg of4chloro-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl-amino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one and 64 mg of 4-chloro-2,5-dimethyl-7-(2,4,6-trimethylyphenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.

¹H NMR (CDCl₃)(4-chloro-2,5,5-trimethyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one) δ 1.61 (s, 6 H), 2.03 (s, 6 H), 2.32 (s, 3 H),2.53 (s, 3 H), 7.00 (s, 2 H) ppm.

¹H NMR (CDCl₃)(4-chloro-2,5-dimethyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one)δ 1.65 (d, 2 H), 2.03 (s, 3 H), 2.06 (s, 3 H), 2.34 (s, 3 H), 2.56 (s, 3H), 3.72 (q, 1 H), 7.00 (s, 2 H) ppm.

B.4-(1-hydroxymethylpropylamino)-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydropyrrolo[2,3d]pyrimidin-6-one

The title compound was prepared by the method of Example 13B from4chloro-2,5,5-trimethyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one) and (S)-2-amino-butanol in dimethylsulfoxide at140° C. ¹H NMR (CDCl₃) δ 1.02 (t, 3H), 1.53 (s, 6 H), 1.5-1.8 (m, 2 H),2.04 (s, 6 H), 2.32 (s, 3 H), 2.38 (s, 3 H), 3.6-3.9 (m, 2 H), 4.0 (m, 1H), 4.5 (d, 1 H), 5.25 (brs, 1 H), 7.00 (s, 2 H) ppm.

EXAMPLE 16

5-Hydroxy-4-(1-hydroxymethylpropylamino)-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5,7-dihydropyrrolo[2,3d]pyrimidin-6-one

The title compound was prepared by the method of Example 13B from4-chloro-2,5-dimethyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyrrodo[2,3-d]pyrimidin-6-one) and(S)-2-amino-butanol in dimethylsulfoxide (DMSO) at 140° C. Twodiastereomers were obtained. The spectra for both diastereomers areshown below:

One isomer: ¹H NMR (CDCl₃) δ 1.03 (t, 3 H), 1.55-1.75 (m, 2 H), 1.77 (s,3 H), 2.05 (s, 3 H), 2.07 (s, 3 H), 2.32 (s, 3 H), 2.37 (s, 3 H),3.55-3.85 (m, 2 H), 4.0 (m, 1 H), 5.1 (d, 1 H), 5.3 (brs, 1 H), 7.00 (s,2 H) ppm.

The other isomer: ¹H NMR (CDCl₃) δ 1.03 (t, 3 H), 1.55-1.75 (m, 2 H),1.73 (s, 3 H), 2.02 (s, 3 H), 2.05 (s, 3 H), 2.32 (s, 3 H), 2.36 (s, 3H), 3.58 (dd, 1 H), 3.77 (dd, 1 H), 4.1 (m, 1 H), 5.03 (d, 1 H), 7.00(s, 2 H) ppm.

EXAMPLE 175-Methoxy-4-(butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one

5-Hydroxy-4-(butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one was prepared by the method analogous to that ofExample 16 starting with4-chloro-2,5-dimethyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one)and N-butyl-ethyl-amine in DMSO at 140° C. Methylation of5-hydroxy-4-(butyl-ethyl-amino)-2,5-dimethyl-7-(2, 4,6-trimethylphenyl)-

5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with sodium hydride and methyliodide using the method of Example 10 provides the title compound. ¹HNMR (CDCl₃) δ 6.97 (d, 2 H), 3.5-4.0 (m, 4 H), 3.23 (s, 3 H), 2.34 (s, 3H), 2.32 (s, 3 H), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.69 (s, 3 H), 1.6-1.8(m, 2 H), 1.3-1.5 (m, 2 H), 1.24 (t, 3 H), 0.99 (t, 3 H) ppm.

EXAMPLE 184-(Butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one

The title compound was prepared by the method analogous to that ofExample 13 (B) starting with4-chloro-2-methyl-7-(2,4,6-trimethylphenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one)and N-butyl-ethyl-amine in DMSO at 135° C. for 2.5 hours to give an oil.¹H NMR (CDCl₃) 7.00 (s, 2 H), 3.85 (s, 2 H), 3.62 (q, 2 H), 3.53 (t, 2H), 2.35 (s, 3 H), 2.32 (s, 3 H), 2.10 (s, 3 H), 1.55-1.70 (m, 2 H),1.35-1.50 (m, 2 H), 1.25 (t, 3 H), 1.00 (t, 3 H) ppm.

EXAMPLE 194-(Butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one

A solution of4-(butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (285 mg, 0.78 mmol) in 5 ml of dry THF wastreated with lithium bis(trimethylsilyl)amide (1.05 mmol) at −78° C. andstirred for 5 minutes. The mixture was quenched with methyl iodide(0.054 ml, 0.858 mmol) at −78° C. After stirring for 10 minutes, themixture was warmed to 0° C. and stirred at that temperature for 20minutes. The mixture was quenched with saturated ammonium chloride andextracted with ethyl acetate. The organic layer was washed with brine,dried and concentrated to give a purple form. The form was purifiedthrough silica gel column chromatography to give4-(butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (120 mg)as a purple glass, 4-(butyl-ethyl-amino)-2,5,5-trmethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one(35 mg) as a purple glass, and 98 mg of a mixture of the two componentsas a purple glass.

¹H NMR (CDCl₃)(4-(butyl-ethyl-amino)-2,5-dimethy-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one) δ 6.96 (s, 2 H), 3.7-3.9 (m, 2 H), 3.51 (q, 1H), 3.15-3.4 (m, 2 H), 2.34 (s, 3 H), 2.30 (s, 3 H), 2.08 (s, 3 H), 2.05(s, 3 H), 1.53 (d, 3 H), 1.5-1.65 (m, 2 H), 1.3-1.4 (m, 2 H), 1.17 (t, 3H), 0.95 (t, 3 H) ppm.

¹H NMR (CDCl₃)(4-butyl-ethyl-amino)-2,5,5-trimethy-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one) δ 6.98 (s, 2 H), 3.45 (q, 2 H), 3.34 (t, 2 H),2.34 (s, 3 H), 2.33 (s, 3 H), 2.06 (s, 6 H), 1.55-1.7 (m, 2 H), 1.3-1.45(m, 2 H), 1.23 (t, 3 H), 0.99 (t, 3 H) ppm.

EXAMPLE 20Butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3d]pyrimidin-4-yl]-ethylamine

A solution of(4-butyl-ethyl-amino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one) (111 mg, 0.292 mmol) in dry THF was treated withlithium aluminum hydride at room temperature. The resulting mixture washeated at reflux for 5 hours. After standard work-up, 97 mg of crudematerial as an oil was obtained. The oil was purified through achromatotron using 10% ethyl acetate in hexane as eluent to givebutyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethylamineas a clear pale yellow oil. ¹H NMR (CDCl₃) δ 6.91 (d, 2 H), 3.7-3.9 (m,2 H), 3.2-3.4 (m, 4 H), 2.5 (q, 1 H), 2.28 (s, 6 H), 2.22 (s, 3 H), 2.05(s, 3 H), 1.5-1.7 (m, 2 H), 1.3-1.5 (m, 5 H), 1.17 (t, 3 H), 0.97 (t, 3H) ppm. High MS (C23H34N4) calc. 366.2776, found 366.27622.

EXAMPLE 214-(Butyl-ethyl-amino)-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-ol

The title compound was prepared by the method of Example 20 startingfrom (4-(butyl-ethyl-amino)-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one)to give a pale yellow solid, mp 142-145° C.; ¹H NMR (CDCl₃) δ 6.95 (d, 2H), 4.90 (s, 1 H), 3.1-3.4 (m, 4 H), 2.4 (brs, 1 H), 2.3 (s, 3 H), 2.31(s, 3 H), 2.21 (s, 3 H), 2.17 (s, 3 H), 1.50 (s, 3 H), 1.45 (s, 3 H),1.25-1.60 (m, 4 H), 1.11 (t, 3 H), 0.93 (t, 3 H) ppm.

EXAMPLE 22Butyl-ethyl-[6-methoxy-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

To a solution of4-(butyl-ethyl-amino)-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-ol (20 mg, 0.05 mmol) in 1 ml of dry THF was treatedwith sodium hydride (60% in oil, 4 mg, 0.1 mmol) and then methyl iodide(0.3 ml) was added at room temperature. After stirring at roomtemperature for 2.5 hours, the mixture was quenched with saturatedammonium chloride and extracted with ethyl acetate. The organic layerwas washed with brine, dried and concentrated to give 26 mg of crudematerial. After silica gel column purification with 10% ethyl acetate inhe mg of a colorless oil of the title compound was obtained. ¹H NMR(CDCl₃) δ 6.92 (s, 1 H), 6.89 (s, 1 H), 4.48 (s, 1 H), 3.1-3.3 (m, 4 H),3.11 (s, 3 H), 2.32 (s, 3 H), 2.28 (s, 3 H), 2.20 (s, 3 H), 2.19 (s, 3H), 1.45 (s, 3 H), 1.44 (s, 3 H), 1.4-1.52 (m, 2 H), 1.2-1.4 (m, 2 H),1.10 (t, 3 H), 0.90 (t, 3 H) ppm.

EXAMPLE 234-(Butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione

To a solution of4-(butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethyphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (76 mg, 0.207 mmol), POCl₃ (0.039 ml, 0.415mmol), triethylamine (0.059 ml), and dimethylamine (1 ml) in 2 mlacetonitrile was heated at reflux for 1 hour. The mixture was quenchedwith water and extracted with ethyl acetate. The organic layer was driedand concentrated to give a brown form (105 mg). After silica gel columnchromatography, the title compound was isolated as a yellow glass (10mg). ¹H NMR (CDCl₃) δ 7.00 (s, 2 H), 3.95-4.15 (m, 2 H), 3.65-3.85 (m, 2H), 2.38 (s, 3 H), 2.32 (s, 3 H), 2.10 (s, 6 H), 1.55-1.75 (m, 2 H),1.35-1.55 (m, 2 H), 1.25 (t, 3 H), 1.00 (t, 3 H) ppm.

EXAMPLE 24N-Butyl-N-ethyl-2,5,N′-trimethyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine

A mixture of(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-methyl-(2,4,6-trimethylphenyl)-amine(200 mg) and N-butyl-ethylamine (0.3 ml) in 1 ml of DMSO was heated inoil bath of 160° C. for 15 hours. The mixture was quenched with waterand extracted with ethyl acetate. The organic layer was separated, driedand concentrated to give the crude material. After silica gel columnpurification using chloroform as eluent, the title compound was obtainedas an oil. ¹H NMR (CDCl₃) δ 6.83 (s, 2 H), 3.22 (s, 3 H), 3.12 (m, 4 H),2.44 (s, 3 H), 2.26 (s, 3 H), 2.01 (s, 6 H), 1.35-1.42 (m, 2 H),1.1-1.25(m, 2 H), 1.00 (t, 3 H), 0.90 (t, 3 H) ppm.

EXAMPLE 25[2,5-Dimethyl(tetrahydrofuran-3-yloxy)-pyrimidin-4-yl]-(2,4,6-trimethylphenyl)-amine

A mixture of 3-hydroxy-tetrahydrofuran (0.5 ml) and sodium hydride (60%in oil, 53 mg, 1.33 mmol) in dry THF was stirred at room temperature for5 minutes, (6-chloro-2,5-dimethyl-pyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine (107 mg, 0.388 mmol) was added. The mixturewas heated at reflux for 15 hours. The mixture was quenched with waterand extracted with ethyl acetate. The organic layer was separated, driedand concentrated to give a yellow oil. The oil was purified throughsilica gel column chromatography using 20% ethyl acetate in hexane aseluent to give 48 mg of the title compound as off-white crystals, mp126-128° C. ¹H NMR (CDCl₃) δ 6.89 (s, 2 H), 5.60 (brs, 2 H), 3.8-4.0 (m,4 H), 2.27 (s, 6 H), 2.13 (s, 6 H), 2.1-2.25 (m, 2 H), 1.93 (s, 3 H)ppm.

EXAMPLE 26

2-(S)-[2,5-Dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidin-4-ylamino]-butan-ol

A mixture of4-chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (30 mg) and2-(S)-amino-1-butanol (0.5 ml) in 0.5 ml of DMSO was heated at 130° C.for 4 hours. The mixture was quenched with water and extracted withethyl acetate. The organic layer was separated, dried and concentratedto give a crude material. The crude residue was purified through silicagel column chromatography to give 24 mg of the title compound as whitecrystals. High MS for (C₁₉H₂₇N₃O₂) calc. 329.2103, found 329.21249;IR(KBr) 3400, 2940, 1580 cm-1; ¹H NMR (CDCl₃) δ 6.841 (s, 2 H), 5.72(brs, 1 H), 4.45 (d, 1 H), 3.82-3.96 (m, 1 H), 3.72-3.9 (m, 1 H),3.5-3.6 (m, 1 H), 2.27 (s, 3 H), 2.21 (s, 3 H), 2.08 (s, 3 H), 2.02 (s,6 H), 1.4-1.7 (m, 2 H), 1.03 (t, 3 H) ppm.

EXAMPLE 274-(1-Ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine

A mixture of 3-pentanol (0.3 ml) and sodium hydride (60% in oil, 32 mg,0.81 mmol) in DMSO was stirred at room temperature for 5 minutes.4-Chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (150 mg,0.54 mmol) was added and the resulting mixture was heated at 150° C. for5 hours. The mixture was quenched with water and extracted with ethylacetate. The organic layer was separated, dried and concentrated to givea beige solid. The solid was purified through silica gel columnchromatography using 20% chloroform in hexane as eluent to give thetitle compound as white crystals, mp 93.5-95.5° C. ¹H NMR (CDCl₃) δ 6.85(s, 2H), 5.11 (t, 1 H), 2.27 (s, 3 H), 2.26 (s, 3 H), 2.11 (s, 3 H),2.03 (s, 6 H), 1.68 (p, 4 H), 0.92 (t, 6 H) ppm.

EXAMPLE 28[[6-(Butyl-N-ethylamino)-2-methylpyrimidin-4-yl]-(2,4,6-trimethylphenyl)-amino]-aceticacid ethyl ester

A mixture of[(6-chloro-2-methylpyrimidin-4-yl-(2,4,6-trimethylpheny)-amino]-aceticacid ethyl ester (85 mg, 0.244 mmol) and N-butyl-ethylamine (0.17 ml,1.1 mmol) in 4 ml DMSO was heated at 135° C. for 15 hours. An additional1 ml of N-butyl-ethylamine was added and the reaction was heated at thattemperature for an additional 15 hours (tlc showed no startingmaterial). The mixture was quenched with water and extracted with ethylacetate. The organic layer was separated, dried and concentrated to give123 mg of a light amber oil. The oil was purified through silica gelchromatotron using 5% ethyl acetate in hexane as eluent to give 92 mg(91%) of the title compound as a white glass. ¹H NMR (CDCl₃) δ 6.94 (s,2 H), 4.69 (s, 1 H), 4.23 (s, 2 H), 4.22 (q, 2 H), 3.35 (q, 2 H), 3.15(t, 2 H), 2.36 (s, 3 H), 2.31 (s, 3 H), 2.21 (s, 6 H), 1.3-1.5 (m, 2 H),1.34 (t, 3 H), 1.1-1.3 (m, 2 H), 1.01 (t, 3 H), 0.80 (t, 3 H) ppm.

EXAMPLE 294-(1-Ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

To a solution of 3-pentanol (0.2 ml, 0.5205 mol) in DMSO (1 ml) wasadded 60% sodium hydride in oil (30 mg) in a portionwise. After stirringat room temperature for 5 min, a solution of4-chloro-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyridine (98 mg) in 0.5ml of dry THF was added and the resulting mixture was heated at 130° C.for 5 hours. The mixture was quenched with water and extracted withethyl acetate. The organic layer was separated, dried and concentratedto give a yellow solid. The solid was purified through silica gel columnchromatography using 20% chloroform in hexane to chloroform as eluent togive 7 mg of the title compound as white crystals, mp 72.5-74° C. ¹H NMR(CDCl₃) δ 6.84 (s, 2 H), 6.26 (s, 1 H), 4.16 (m, 1 H), 2.27 (s, 3 H),2.17 (s, 6 H), 2.04 (s, 6 H), 1.69 (m, 4 H), 0.95 (t, 6 H) ppm.

The mesylate salt of4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridinewas prepared by addition of 1 equivalent of methanesulfonic acid inethyl acetate. The white crystals formed from ethyl acetate. Mp 117-119°C.

EXAMPLE 30[6-(Butyl-ethyl-amino)-2,5-dimethylpyrimidin-4-yl]-(2,4,6-trimethylphenyl)-acetonitrile

A solution of mesitylacetonitrile (66 mg, 0.41 mmol) in 1 ml of DMSO wastreated with NaH (60% in oil, 20 mg, 0.50 mmol) and stirred at roomtemperature for 20 minutes,butyl-(6-chloro-2,5-dimethylpyrimidin-4-yl)-ethylamine (100 mg, 0.414mmol) was added and the resulting mixture was heated at 130° C. for 15hours. The mixture was quenched with water and extracted with ethylacetate. The organic layer was separated, dried and concentrated to give160 mg of brown oil. The oil was purified through silica gel columnchromatography using 5% ethyl acetate in hexane as eluent to give thetitle compound as a brown oil. ¹H NMR (CDCl₃) δ 6.83 (s, 2 H), 5.49 (s,¹H), 3.2-3.4 (m, 2 H), 3.0-3.2 (m, 2 H), 2.51 (s, 3 H), 2.24 (s, 3 H),2.21 (s, 6 H), 1.66 (s, 3 H), 1.35-1.50 (m, 2 H), 1.1-1.3 (m, 2 H), 1.05(t, 3 H), 0.84 (t, 3 H) ppm.

EXAMPLE 312-[6-(1-Ethyl-propoxy)-2,5-dimethylpyrimidin-4-yl]-2-(2,4,6-trimethylphenyl)-propionitrile

To a solution of 3-pentanol (140 mg, 1.59 mmol) in 2 ml of dry THF wasadded sodium hydride (60% in oil, 38 mg) and the mixture was stirred atroom temperature for 5 minutes.2-(6-Chloro-2,5-dimethylpyrimidin-4-yl)-2-(2,4,6-trimethylphenyl)-propionitrile (100 mg, 0.319 mmol) was added to thereaction mixture, and the resulting mixture was heated at reflux for 4hours. The mixture was quenched with water and extracted with ethylacetate. The organic layer was separated, dried and concentrated to givea brown oil (170 mg). The residue was purified through chromatotronusing 20% ethyl acetate in hexane as eluent to give a mixture of twoisomers as a yellow glass form and both having a M+ of 365 from GC/Ms.¹H NMR (CDCl₃) δ 6.8 and 6.76 (s, 2 H), 4.08 and 3.96 (m, ¹H), 3.25 and3.22 (s, 3 H), 2.36 and 2.30 (s, 3 H), 2.21, 2.20 and 2.06 (s, total of9 H), 1.5-1.7 (m, 4 H), 1.04 (s, 3 H), 0.96 and 0.90 (t, 3 H) ppm.

EXAMPLE 324-(1-Ethyl-propoxy)-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine

The title compound was prepared by the method analogous to that inExample 32 starting with4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine and3-pentanol. White crystals, mp. 82-84° C.

The title compounds of Example 33-39 were prepared by a method analogousto that of Example 27, starting with the appropriate4-chloro-2-methyl-5-substituted 6-substituted-phenoxy)-pyrimidine and3-pentanol.

EXAMPLE 334-(2,4-Dimethyl-phenoxy)-6-(1-ethyl-propoxy)-2,5-dimethyl-pyrimidine

¹H NMR (CDCl₃) δ 6.8-7.0 (m, 3 H), 5.13 (m, 1 H), 2.30 (s, 6 H), 2.10(s, 3 H), 2.09 (s, 3 H), 1.68 (m, 4 H), 0.92 (t, 6 H) ppm.

EXAMPLE 344-(2,6-Dimethyl-phenoxy)-6-(1-ethyl-propoxy)-2,5-dimethyl-pyrimidine

¹H NMR (CDCl₃) δ 7.04 (m, 3 H), 5.12 (m, 1 H), 2.25 (s, 3 H), 2.13 (s, 3H), 2.07 (s, 6 H), 1.66 (m, 4 H), 0.92 (t, 6 H) ppm.

EXAMPLE 354-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine-5-carbonitrile

mp 128-130° C., ¹H NMR (CDCl₃) δ 6.8 (s, 2 H), 5.18 (m, 1 H), 2.30 (s, 3H), 2.21 (s,3 H), 2.00 (s,6 H), 1.4-1.58 (m, 4 H), 0.90 (t, 6 H) ppm.

EXAMPLE 365-tert-Butyl-4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine

¹H NMR (CDCl₃) δ 6.85 (s, 2 H), 5.25 (m, 1 H), 2.29 (s, 3 H), 2.20 (s, 3H), 2.03 (s, 6 H), 1.65-1.80 (m, 4 H), 1.52 (s, 9 H), 0.90 (t, 6 H) ppm.

EXAMPLE 374-(1-Ethyl-propoxy)-5-isopropyl-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine

¹H NMR (CDCl₃) δ 6.85 (s, 2 H), 5.17 (m, 1 H), 3.50 (m, 1 H), 2.27 (s, 3H), 2.23 (s, 3 H), 2.03 (s, 6 H), 1.69 (m, 4 H), 1.33 (s, 3 H), 1.31 (s,3 H), 0.92 (t, 6 H) ppm.

EXAMPLE 385-Bromo-4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine

¹H NMR (CDCl₃) δ 6.86 (s, 2 H), 5.16 (m, 1 H), 2.29 (s, 3 H), 2.28 (s, 3H), 2.06 (s, 6 H), 1.65-1.80 (m, 4 H), 1.52 (s, 9 H), 0.95 (t, 6 H) ppm.

EXAMPLE 395-Chloro-4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine

¹H NMR (CDCl₃) δ 6.86 (s, 2 H), 5.16 (m, 1 H), 2.28 (s, 3 H), 2.27 (s, 3H), 2.06 (s, 6 H), 1.65-1.80 (m, 4 H), 1.52 (s, 9 H), 0.94 (t, 6 H) ppm.

The title compounds of Examples 40-41 were prepared by a methodanalogous to that described in Example 24, starting from4chloro-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine and theappropriate amine.

EXAMPLE 40[2,5-Dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-propyl)-amine

¹H NMR (CDCl₃) δ 6.84 (s, 2 H), 4.10 (m, 2 H, NH and CH), 2.27 (s, 3 H),2.21 (s, 3 H), 2.04 (s, 9 H), 1.3-1.6 (m, 4 H), 0.91 (t, 6 H) ppm.

EXAMPLE 41Butyl-[2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl]-ethyl-amine

¹H NMR (CDCl₃) δ 6.87 (s, 2 H), 3.76 (m, 2 H), 3.68 (t, 2 H), 2.73 (s, 3H), 2.28 (s, 6 H), 1.99 (s, 6 H), 1.5-1.7 (m, 4 H), 1.27 (t, 3 H), 0.94(t, 3 H) ppm.

The title compounds of Examples 42-54 were prepared by a methodanalogous to that described in Example 29, starting with the appropriate4-chloro-2-methyl-6-(substituted phenoxy or thiophenoxy)-pyridine andthe appropriate alcohol.

EXAMPLE 422-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine

¹H NMR (CDCl₃) δ 7.18 (s, 2 H), 6.30 (s, 1 H), 4.22 (m, 1 H), 2.20 (s, 6H), 2.05 (s, 6 H), 1.73 (m, 4 H), 1.00 (t, 6 H) ppm.

EXAMPLE 432-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine

¹H NMR (CDCl₃) δ 7.05 (s, 2 H), 6.31 (s, 1 H), 4.20 (m, 1 H), 2.20 (s, 6H), 2.08 (s, 6 H), 1.73 (m, 4 H), 0.99 (t, 6 H) ppm.

EXAMPLE 443-Ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

¹H NMR (CDCl₃) δ 6.85 (s, 2 H), 6.26 (s, 1 H), 4.18 (m, 1 H), 2.73(q,2H), 2.28 (s, 3 H), 2.17 (s, 3 H), 2.05 (s, 6 H), (m, 4 H), 1.18 (t, 3H), 0.96 (t, 6 H) ppm.

EXAMPLE 454-(1-ethyl-propenyloxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine(A mixture of cis and trans isomers)

¹H NMR (CDCl₃) δ 6.85 (s, 2 H), 6.30 (s, 0.3 H), 6.21 (s, 0.7 H), 5.10(m, 0.7 H), 4.95 (m, 0.3 H), 2.27 (s, 3 H), 2.24 (s, 2.1 H), 2.19 (s,0.9 H), 2.14 (s, 3 H), 2.05 (s, 6 H), 1.65 (d, 0.9 H), 1.50 (d, 2.1 H),1.08 (t, 1.8 H), 1.05 (t, 4.2 H) ppm.

EXAMPLE 46 Methanesulfonic acid salt of4-(1-ethyl-propoxy)-2,3,5-trimethyl-6-(2,4,6-trimethyl-phenoxy)-pyridine

Mp 58-60° C. ¹H NMR (CDCl₃) δ 6.90 (s, 2 H), 4.20 (m, 1 H), 2.70 (s, 3H), 2.61 (s, 3 H), 2.28 (s, 3 H), 2.16 (s, 3 H), 2.08 (s, 6 H), 1.5-1.8(m, 4 H), 0.96 (t, 6 H) ppm.

EXAMPLE 474-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acidmethyl ester

¹H NMR (CDCl₃) δ 6.84 (s, 2 H), 6.39 (s, 1 H), 5.04 (m, 1 H), 3.85 (s, 3H), 2.27 (s, 3 H), 2.23 (s, 3 H), 2.05 (s, 6 H), 1.5-1.7 (m, 4 H), 0.95(s, 6 H) ppm.

EXAMPLE 484-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridine

¹H NMR (CDCl₃) δ 6.90 (s, 2 H), 6.34 (d, J-2 Hz,1 H), 5.70 (d, J=2 Hz,1H), 4.05 (m, 1 H), 2.40 (s, 3 H), 2.30 (s, 3 H), 2.11 (s, 6 H), 1.62 (m,4 H), 0.89 (t, 6 H) ppm.

EXAMPLE 493,6-Dimethyl-4-(tetrahydro-furan-3-yloxy)-2-(2,4,6-trimethyl-phenoxy)-pyridine

¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 6.25 (s, 1 H), 4.99 (m, 1 H), 3.9-4.1(m, 4 H), 2.31 (s, 3 H), 2.23 (s, 3 H), 2.20 (s, 3 H), 2.1-2.3 (m, 2 H),2.07 (s, 6 H) ppm.

EXAMPLE 504-(1-Methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 6.38 (s, 1 H), 4.42 (m, 1 H), 3.5-3.7(m, 2 H), 3.42 (s, 3 H), 2.31 (s, 3 H), 2.21 (s, 6 H), 2.07 (s, 6 H),1.7-1.85 (m, 2 H), 1.02 (t, 3 H) ppm.

EXAMPLE 513-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yloxy]-pentan-2-ol

¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 6.34 (s, 1 H), 4.25-4.45 (m, 1 H0,3.6-3.8 (m, ¹H), 2.30 (s, 3 H)2.21 (s, 3 H), 2.20 (s, 3 H), 2.06 (s, 6H), 1.2-1.4 (m, 5 H0, 1.07 (t, 3 H) ppm.

EXAMPLE 524-sec-Butoxy-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 6.31 (s, 1 H), 4.35 (m, 1 H), 2.30 (s, 3H), 2.21 (s, 3 H), 2.19 (s, 3 H), 2.07 (s, 6 H0, 1.7-1.9 (m, 2 H), 1.34(d, 3 H), 1.01 (t, 3 H) ppm.

EXAMPLE 532-(2,4-Dimethyl-phenylsulfanyl)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine

Golden oil. ¹H NMR (CDCl₃) δ 7.19 (d, j=8 Hz,1 H0, 7.06 (s, 1 H), 6.94(d, J=8 Hz,1 H), 6.42 (s, 1 H), 4.19 (m, 1 H), 2.34 (s, 3 H), 2.33 (s, 3H), 2.32 (s, 3 H), 2.18 (s, 3 H), 1.69 (m, 4 H), 0.95 (t, 6 H) ppm.

EXAMPLE 54

4-(1-Ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridine¹H NMR (CDCl₃) δ 6.97 (s, 2 H), 6.30 (s, 1 H), 4.15 (m, 1 H), 2.35 (s, 6H), 2.30 (s, 3 H), 2.23 (s, 3 H), 2.20 (s, 3 H), 1.68 (m, 4 H), 0.95 (t,6 H) ppm.

EXAMPLE 552-(4-Ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine

To a solution of 2.5 N n-BuLi in hexane (0.47 ml, 1.18 mmol) in 5ml ofdry THF was added a solution of2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-prpoxy)-3,6-dimethyl-pyridine(465 mg, 1.18 mmol) in 5 ml of dry THF at −78° C. After stirring at thattemperature for 5 min, an excess of ethyl iodide (0.4 ml) was added andthe resulting mixture was stirred at −78° C. for 30 min, then at 0° C.for 15 min. The mixture was quenched with saturated ammonium chlorideand extracted with ethyl acetate. The organic layer was dried andconcentrated to give a light brown oil The oil was puriified throughsilica gel column chromatography using chloroform as eluent to give 260mg of the title compound as white solid. ¹H NMR (CDCl₃) δ 6.90 (s, 2 H),6.38 (s, 1 H), 4.20 (m, 1 H), 2.61(q,2 H), 2.24 (s, 3 H), 2.21 (s, 3 H),2.10 (s, 6 H), 1.70 (m, 4 H), 1.30 (t, 3 H), 0.98 (t, 6 H) ppm.

The title compounds of Examples 56-62 were prepared by a methodanalogous to that described in Example 55, starting from n-BuLi and2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-prpoxy)-3,6-dimethyl-pyridine,followed by quenching with an appropriate electrophile.

EXAMPLE 564-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde

¹H NMR (CDCl₃) δ 9.94 (s, 1 H), 7.61 (s, 2 H), 6.32 (s, 1 H), 4.20 (m, 1H), 2.21 (s, 3 H), 2.16 (s, 9 H)1.70 (m, 4 H), 0.98 (t, 6 H) ppm.

EXAMPLE 572-(2,6-Dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine

¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 6.30 (s, 1 H), 4.20 (m, 1 H), 2.54(dd,2H), 2.22 (s, 3 H), 2.20 (s, 3 H), 2.09 (s, 6 H), 1.6-1.8 (m, 6 H),0.9-1.1 (m, 9 H) ppm.

EXAMPLE 582-(2,6-Dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine

¹H NMR (CDCl₃) δ 7.06 (m, 3 H), 6.30 (s, 1 H), 4.20 (m, 1 H), 2.21 (s, 6H), 2.11 (s, 6 H), 1.73 (m, 4 H), 0.99 (t, 6 H) ppm.

EXAMPLE 592-{4-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl)-propan-2-ol

¹H NMR (CDCl₃) δ 7.15 (s, 2 H), 6.25 (s, 1 H), 4.20 (m, 1 H), 2.20 (s, 3H), 2.19 (s, 3 H), 2.10 (s, 6 H), 1.85 (brs, ¹H),1.70 (m, 4 H), 1.60 (s,6 H), 0.95 (t, 6 H) ppm.

EXAMPLE 604-(1-Ethyl-propoxy)-2-(4-iodo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

¹H NMR (CDCl₃) δ 7.39 (s, 2 H), 6.30 (s, 1 H), 4.19 (m, 1 H), 2.20 (s, 3H), 2.18 (s, 3 H), 2.05 (s, 6 H), 1.72 (m, 4 H), 0.98 (t, 6 H) ppm.

EXAMPLE 614-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol

¹H NMR (CDCl₃) δ 7.85 (brs, 1 H), 6.36 (s, 1 H), 6.24 (s, 2 H), 4.24 (m,1 H), 2.39 (s, 3 H), 2.20 (s, 3 H), 2.02 (s, 6 H), 1.74 (m, 4 H), 1.00(t, 6 H) ppm.

EXAMPLE 621-{4-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl)-pyrrolidin-2-one

¹H NMR (CDCl₃) δ 7.30 (s, 2 H), 6.30 (s, 1 H), 4.20 (m, 1 H), 3.88 (t, 2H), 2.61 (t, 2 H) ppm.

EXAMPLE 63{4-[4-(1Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanol

A mixture of4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde(114 mg, 0.41 mmol) and sodium borohydride (63 mg, 1.6 mmol) in 3 ml ofmethanol was stirred at room temperature for 2 hours. The reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried and concentrated to give yellow oil. The oil waspurified through silica gel using chloroform as eluent to give 70 mg ofthe title compound as a colorless oil. ¹H NMR (CDCl₃) δ 7.04 (s, 2 H),6.32 (s, 1 H), 4.55 (s, 2 H), 4.21 (m, 1 H), 2.30 (brs, 1 H), 2.22 (s, 3H), 2.21 (s, 3 H), 2.12 (s, 6 H), 1.73 (m, 4 H), 0.91 (t, 6 H) ppm.

EXAMPLE 644-(1-Ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

To a solutionof4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol(40 mg, 0.12 mmol) in 3 ml of dry THF was added 10 mg of 60% sodiumhydride in oil at room temperature. After stirring for 5 min, 0.3 ml ofmethyl iodide was added and the resulting mixture was stirred at roomtemperature overnight. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was dried and concentrated to givea yellow solid. The solid was purified through silica gel columnchromatography using hexane to 1:1 chloroform:hexane as eluent to yield20 mg of the Utle compound as yellow solid. ¹H NMR (CDCl₃) δ 6.66 (s, 2H), 6.28 (s, 1 H), 4.20 (m, 1 H), 3.79 (s, 3 H), 2.20 (s, 3 H), 2.19 (s,3 H0, 2.08 (s, 6 H), 1.71 (m, 4 H), 0.97 (t, 6 H) ppm.

EXAMPLE 654-(1-Ethyl-propoxy)-2-(4-isopropoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

To a solution of4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol(58 mg, 0.176 mmol) in 3 ml of dry THF was added triphenylphosphine (70mg, 0.264 mmol) and isopropanol (60 mg, 0.22 mmol). The resultingmixture was stirred at room temperature for 5 min, diethylazodicarboxylate (46 mg, 0.264 mmol) was added. The mixture was stirredat room temperature overnight. An additional 20 mg of diethylazodicarboxylate was added and the mixture was stirred for an additional4 hours. The mixture was quenched with water and extracted withmethylene chloride. The organic layer was dried and concentrated to givean oil. The oil residue was purified through silica gel columnchromatography using 1:1 hexane:chloroform to 1:2 hexane: chloroform aseluent to give 38 mg (58%) of the title compound as a colorless oil. ¹HNMR (CDCl₃) δ 6.60 (s, 2 H), 6.28 (s, 1 H), 4.50 (m, 1 H), 4.18 (m, 1H), 2.20 (s, 3 H), 2.19 (s, 3 H), 2.079s,6 H), 1.71 (m, 4 H), 1.34 (d, 6H), 0.98 (t, 6 H) ppm.

The title compounds of Examples 66-67 were prepared by a methodanalogous to that described in Example 64, starting with an appropriatepyridine-3,5-dimethylphenol or pyridine-3,5-dimethyl-phenyl methanolwith a base, followed by quenching with an appropriate alkyl halide.

EXAMPLE 662-(4-Ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine

¹H NMR (CDCl₃) δ 6.60 (s, 2 H), 6.28 (s, 1 H), 4.19 (m, 1 H), 3.99(q,2H), 2.19 (s, 3 H), 2.18 (s, 3 H), 2.07 (s, 6 H), 1.74 (m, 4 H), 1.40 (t,3 H), 0.97 (t, 6 H) ppm.

EXAMPLE 674-(1-Ethyl-propoxy)-2-(4-methoxymethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

Mp 58-60° C. ¹H NMR (CDCl₃) δ 7.05 (s, 2 H), 6.30 (s, 1 H), 4.41 (s, 2H), 4.19 (m, 1 H), 3.42 (s, 3 H), 2.21 (s, 3 H), 2.18 (s, 3 H), 2.11 (s,6 H), 1.72 (m, 4 H), 0.98 (s, 6 H) ppm.

EXAMPLE 68[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine

A mixture of 4-chloro-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine(1.330 g, 4.822 mmol) and 20 ml of ethyl amine in 13 ml of1-methyl-2-pyrrolidinone was heated at 150° C. at 250 psi overnight in apressure reactor. The reaction was heated an additional 24 hours at 175°C. and 300 psi. The reaction mixture cooled to room temperature anddiluted with water and extracted with ethyl acetate. The organic layerwas dried and concentrated to give a brown oil. The oil residue waspurified through silica gel column chromatography using chloroform to 2%methanol in chloroform as eluent to give 0.820 g (60%) of the titlecompound as a white solid, mp 115-116° C.

¹H NMR (CDCl₃)δ 6.87 (s, 2 H), 6.11 (s, 1 H), 3.85 (t, 1 H), 3.24 (m, 2H), 2.30 (s, 3 H), 2.17 (s, 3 H), 2.13 (s, 3 H), 2.08 (s, 6 H), 1.32 (t,3 H) ppm.

The title compounds of Examples 69-71 were prepared by the methodanalogous to that described in Example 68 starting with an appropriate4-chloro-2-substituted phenoxy-pyridine and an appropriate amine.

EXAMPLE 69[3,6-Dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-(1-ethyl-propyl)-amine

Mp 108-110° C. ¹H NMR (CDCl₃) δ 6.95 (s, 2 H), 6.09 (s, 1 H), 3.63 (d, 1H), 3.28 (m, 1 H), 2.36 (s, 6 H), 2.30 (s, 3 H), 2.17 (s, 3 H), 2.11 (s,3 H), 1.4-1.75 (m, 4 H0, 0.93 (t, 6 H) ppm. The hydrogen chloride salt,mp 148-150° C.; ¹H NMR (CDCl₃) δ 6.95 (s, 2 H), 6.30 (s, 1 H), 5.75 (d,¹H), 3.38 (m, 1 H), 2.69 (s, 3 H), 2.33 (s, 6 H), 2.28 (s, 3 H0, 2.02(s, 3 H), 1.72 (m, 4 H), 0.93 (t, 6 H) ppm.

EXAMPLE 702-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine;white solid

¹H NMR (CDCl₃) δ 7.04 (s, 2 H), 6.13 (s, 1 H), 3.88 (t, 1 H), 3.24 (m, 2H), 2.17 (s, 3 H), 2.17 (s, 3 H), 2.08 (s, 6 H), 1.32 (t, 3 H) ppm.

EXAMPLE 71[3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)pyridin-4-yl]-ethyl-amine

Tan crystals, mp 114-116° C. ¹H NMR (CDCl₃) δ 6.94 (s, 2 H), 6.12 (s, 1H), 3.76 (t, 1 H), 3.21 (m, 2 H), 2.35 (s, 6 H), 2.30 (s, 3 H), 2.19 (s,3 H), 2.10 (s, 3 H), 1.29 (t, 3 H) ppm.

EXAMPLE 72[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine

To a solution of[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine(7.00 g, 24.6 mmol) in 100 ml of dry THF was added 1.0 M lithiumbis(trimethylsilyl)amide in hexane (32 ml, 32 mmol) at −78° C. Afterstirring at that temperature for 10 min, the reaction mixture wastreated with iodopropane (13 ml, 125 mmol) at −70° C. After stirring atthat temperature for 20 min, the dry ice bath was removed and thereaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was dried and concentrated to give an oil.The oil residue was purified through silica gel column chromatographyusing 1:1 chloroform:hexane to chloroform as eluent to give 5.04 g(62.5%) of[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amineas yellow solid; ¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 6.41 (s, 1 H), 3.11(q,2H), 3.03(dd,2 H), 2.30 (s, 3 H), 2.25 (s, 3 H), 2.19 (s, 3 H), 2.07 (s,6 H), 1.55 (m, 2 H), 1.08 (t, 3 H), 0.90 (t, 3 H) ppm. The correspondingHCl salt, white crystals; mp167-169° C.; ¹H NMR (MeOH-d4) δ 7.00 (s, 2H), 6.75 (s, 1 H), 3.54(q,2 H), 3.43 (t, 2 H), 2.35 (s, 3 H), 2.31 (s, 3H), 2.27 (s, 3 H), 2.08 (s, 6 H), 1.69 (m, 2 H), 1.25 (t, 3 H0, 0.94 (t,3 H) ppm;

The title compounds of Examples 73-79 were prepared by the methodanalogous to that described in Example 72 starting with an appropriate2-(substituted phenoxy or thiophenoxy) pyridin-4-yl-ethyl amine and abase (lithium bis(trimethylsilyl)amide or lithium diisopropylamide),followed by quenching with an appropriate alkyl halide.

EXAMPLE 73[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-diethyl-amine

¹H NMR (CDCl₃) δ 6.87 (s, 2 H), 6.40 (s, 1 H), 3.10(q,4 H), 2.30 (s, 3H), 2.24 (s, 3 H), 2.19 (s, 3 H), 2.06 (s, 6 H), 1.08 (t, 6 H) ppm. TheHCl salt, white crystals, mp 180-181° C.; ¹H NMR (CD₃OD) δ 7.01 (s, 2H), 6.78 (s, 1 H), 3.58(q,4 H), 2.38 (s, 3 H), 2.32 (s, 6 H), 2.10 (s, 6H), 1.28 (t, 6 H) ppm.

EXAMPLE 74[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-methyl-amine

¹H NMR (CDCl₃) δ 6.86 (s, 2 H), 6.38 (s, 1 H), 3.05(q,2 H), 2.75 (s, 3H), 2.29 (s, 3 H), 2.25 (s, 3 H), 2.18 (s, 3 H), 2.06 (s, 6 H), 1.18 (t,3 H) ppm. The HCl salt, mp 173-174° C.

EXAMPLE 75Butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine

¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 6.41 (s, 1 H), 3.0-3.3 (m, 4 H), 2.31(s, 3 H), 2.25 (s, 3 H), 2.19 (s, 3 H), 2.08 (s, 6 H), 1.3-1.6 (m, 4 H),1.09 (t, 3 H), 0.93 (t, 3 H) ppm.

EXAMPLE 76Butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine

¹H NMR (CDCl₃) δ 7.03 (s, 2 H), 6.39 (s, 1 H), 3.09(q,2 H), 3.01(dd,2H), 2.21 (s, 3 H), 2.16 (s, 3 H), 2.05 (s, 6 H), 1.4-1.6 (m, 2 H),1.25-1.40(m, 2 H), 1.06 (t, 3 H), 0.87 (t, 3 H) ppm. The HCl salt, mp177-178° C.; ¹H NMR(DMSO-d6) δ 7.20 (s, 2 H), 6.74 (s, 1 H), 3.1-3.4 (m,4 H), 2.24 (s, 3 H), 2.17 (s, 3 H), 2.00 (s, 6 H), 1.4-1.6 (m, 2 H),1.25-1.40 (m, 2 H), 1.05 (t, 3 H), 0.86 (t, 3 H) ppm.

EXAMPLE 77[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-propyl-amine

¹H NMR (CDCl₃) δ 7.04 (s, 2 H), 6.41 (s, 1 H), 3.11(q,2 H), 3.00 (m, 2H), 2.24 (s, 3 H), 2.17 (s, 3 H), 2.07 (s, 6 H), 1.54 (m, 2 H), 1.08 (t,3 H), 0.90 (t, 3 H) ppm. The HCl salt, white crystals, mp 74-76° C. ¹HNMR(CD3OD) δ 7.23 (s, 2 H), 6.81 (s, 1 H), 3.58(q,2 H), 3.46 (m, 2 H),2.38 (s, 3 H), 2.31 (s, 3 H), 2.13 (s, 6 H), 1.6-1.8 (m, 2 H), 1.26 (t,3 H), 0.96 (t, 3 H) ppm.

EXAMPLE 78[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-diethyl-amine

¹H NMR (CDCl₃) δ 7.05 (s, 2 H), 6.41 (s, 1 H), 3.11(q,4 H), 2.24 (s, 3H), 2.18 (s, 3 H), 2.07 (s, 6 H), 1.09 (t, 6 H) ppm. The HCl salt, whitecrystals, mp 184-185° C. ¹H NMR(CD3OD) δ 7.23 (s, 2 H), 6.81 (s, 1 H),3.56(q,4 H), 2.37 (s, 3 H), 2.33 (s, 3 H), 2.12 (s, 6 H), 1.26 (t, 6 H)ppm.

EXAMPLE 79[3,6-Dimethyl-[2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4-yl]-ethyl-propyl-amine

¹H NMR (CDCl₃) δ 6.95 (s, 2 H), 6.45 (s, 1 H), 3.02 (q,2 H), 2.97 (dd,2H), 2.35 (s, 6 H), 2.31 (s, 3 H), 2.21 (s, 3 H), 2.20 (s, 3 H), 1.49 (m,2 H), 1.02 (t, 3 H), 0.86 (t, 3 H) ppm. The HCl salt, white crystals, mp110-112° C.; ¹H NMR (CDCl₃) δ 6.92 (s, 2 H), 6.51 (s, 1 H), 3.27 (q,2H), 3.19 (dd,2 H), 284 (s, 3 H), 2.32 (s, 6 H), 2.28 (s, 3 H), 1.82 (s,3 H), 1.52 (m, 2H), 1.15 (t, 3H), 0.84 (t, 3H) ppm.

EXAMPLE 80N-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-ethyl-2,2,2-trifluoro-acetamide

To a solution of[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine (200mg, 0.7 mmol) in dry methylene chloride was added triethylamine (0.1 ml,0.73 mmol) and trifluoroacetic anhydride (0.11 ml, 0.74 mmol) andstirred at room temperature for 2 hours. The reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas dried and concentrated to give the crude material . The crudematerial was purified through silica gel column chromatography using 25%hexane in chloroform as eluent to give 225 mg (83%) of the titlecompound as white crystals, mp 110-111° C., ¹H NMR (CDCl₃) δ 6.91 (s, 2H), 6.57 (s, 1 H), 4.16 (m, 1 H), 3.39 (m, 1 H), 2.32 (s, 3H), 2.27 (s,3 H), 2.24 (s, 3 H), 2.07 (s, 3 H), 2.05 (s, 3 H), 1.26 (t, 3 H) ppm.

EXAMPLE 813,6-Dimethyl-2)-2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine

To a solution ofN-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-ethyl-2,2,2-trifluoro-acetamide(292 mg, 0.77 mmol) in 15 ml of dry THF was added 2M BH₃.DMS in THF(0.96 ml, 1.92 mmol) at room temperature. The resulting mixture washeated at reflux overnight. The mixture was quenched with water andextracted with ethyl acetate. The organic layer was dried andconcentrated to give 300 mg of white solid. The solid was recrystallizedfrom hexane and 2 drops of methanol to give white crystals (298 mg,96%). ¹H NMR (CDCl₃) δ 6.85 (s, 2 H), 6.47 (s, 1 H), 3.70 (q,2 H), 3.25(q,2 H), 2.32 (s, 3 H), 2.27 (s, 3 H), 2.20 (s, 3 H), 2.05 (s, 3 H),1.13 (t, 3 H) ppm. The HCl salt, white crystals, mp 73-74° C. ¹HNMR(CD₃OD) δ 6.97 (s, 1 H), 6.96 (s, 2 H), 4.09 (q,2 H), 3.46 (q,2 H),2.34 (s, 3 H), 2.30 (s, 3 H), 2.28 (s, 3 H), 2.05 (s, 6 H), 1.17 (t, 3H) ppm.

EXAMPLE 824-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester (500 mg, 1.56 mmol) and 1-ethyl-propyl-amine (0.8 ml)in 1 ml of DMSO was heated at reflux for 15 hours. The mixture wasquenched with sat. ammonium chloride and extracted with ethyl acetate.The organic layer was dried and concentrated to give 445.6 mg of yellowsolid. The solid was purified through silica gel column chromatographyusing 1:1 ratio of chloroform:hexane as eluent to give (289 mg, 50%)ofthe title compound as white crystals, mp 98-102° C.; ¹H NMR (CDCl₃) δ8.04 (d, 1 H), 6.85 (s, 2 H), 6.06 (s, 1 H), 3.85 (s, 3 H), 3.32 (m, 1H), 2.28 (s, 3 H), 2.10 (s, 3 H), 2.07 (s, 3 H), 1.62 (m, 4 H), 0.95 (t,6 H) ppm.

EXAMPLE 834-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol

A mixture of4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)nicotinicacid methyl ester (220 mg, 0.594 mmol) and 1 M lithium aluminum hydridein THF (4 ml, 4 mmol) in dry THF (3 ml) was heated at reflux for 10 min,then stirred at rt ovemight. The mixture was quenched with 0.3 ml ofwater, 0.3 ml of 2N NaOH, then 0.8 ml of water and stirred at roomtemperature for 10 min. White solid formed and was filtered throughcelite. The filtrate was concentrate to dryness to give 207 mg (100%) ofthe title compound as white solid. ¹H NMR (CDCl₃) δ 6.83 (s, 2 H), 6.06(s, 1 H), 4.96 (d, 1 H,NH), 4.88 (d, 2 H), 3.28 (m, 1 H), 2.26 (s, 3 H),2.11 (s, 3 H), 2.04 (s, 6 H), 1.4-1.6 (m, 4 H), 1.4 (t, 1 H,OH), 0.93(t, 6 H) ppm.

EXAMPLE 844-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid

A mixture of4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester (16 mg, 0.043 mmol) and lithium hydroxide (30 mg) indioxane (1 ml) and water (1 ml) was stirred at rt over night. Themixture was quenched with water and adjusted to pH 7.0 and extractedwith chloroform. The organic layer was dried and concentrated to givethe crude material. The crude material was purified through silica gelcolumn chromatography using 10% ethyl acetate in chloroform as eluent togive 7 mg of the ttle compound as white solid. ¹H NMR (CDCl₃) δ 9.12 (d,1 H), 6.87 (s, 2 H), 6.16 (s, 1 H), 3.35 (m, 1 H), 2.29 (s, 3 H), 2.10(s, 3 H), 2.07 (s, 6 H), 1.4-1.6 (m, 4 H), 0.94 (t, 6 H) ppm.

EXAMPLE 85[3-Chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-aminehydrogen chloride

To a solution of4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol(40 mg, 0.117 mmol) in 0.3 ml of dry methylene chloride was addedthionyl chloride (o.15 ml) and stirred at rt for 1 hr. The mixture wasconcentrated to dryness and pumped in vacuo to give white glass form.The glass form was trituated with ether to give the title compound (47mg, 100%) as a white solid. ¹H NMR (CDCl₃) δ 6.92 (s, 2 H), 6.24 (s, 1H), 5.50 (d, 1 H), 4.72 (s, 2 H), 3.50 (m, 1 H), 2.73 (s, 3 H), 2.27 (s,3 H), 2.15 (s, 6 H), 1.5-1.8 (m, 4 H), 0.97 (t, 6 H) ppm.

EXAMPLE 86[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine

To a solution of[3-Chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine(35 mg, 0.088 mmol) in dry THF (0.5 ml) was added1M lithium aluminumhydride in THF (0.3 ml, 0.3 mmol) and the resulting mixture was stirredat rt for 1.5 hours. The mixture was quenched with 0.1 ml of water, 0.1ml of 2N NaOH and 0.3 ml of water and stirred for 5 min. The mixture wasfiltered and washed with THF. The filtrate was concentrated to dryness.The residue was dissolved in chloroform and dried over anhydrous sodiumsulfate, filtered, and concentrated to dryness to give 28 mg (100%) ofoil. The oil was purified through silica gel column chromatography usingchloroform as eluent to give 26 mg of the title compound as an oil. ¹HNMR (CDCl₃) δ 6.85 (s, 2 H), 6.08 (s, 1 H), 3.72 (d, NH,1 H), 3.35 (m, 1H), 2.30 (s, 3 H), 2.16 (s, 3 H), 2.13 (s, 3 H), 2.05 (s, 6 H),1.45-1.75 (m, 4 H), 0.98 (t, 6 H) ppm. The corresponding HCl salt wasprepared and trituated with ether to give 20 mg of white solid. ¹H NMR(CDCl₃) δ 6.88 (s, 2 H), 6.19 (s, 1 H), 4.98 (brs, 1 H), 3.50 (m, 1 H),2.71 (s, 3 H), 2.26 (s, 3 H), 2.12 (s, 6 H), 2.00 (s, 3 H), 1.5-1.8 (m,4 H), 0.95 (t, 6 H) ppm.

EXAMPLE 87(1-Ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

To a solution of4-(1-ethyl-propylamino-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol(46 mg, 0.134 mmol) in dry THF (0.5 ml) was added 60% sodium hydride inoil (6 mg, 0.134 mmol) and stirred for 2 min. Methyl iodide (0.1 ml) wasadded and the mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was dried and concentrated to give the titlecompound as an oil (40 mg, 84%). ¹H NMR (CDCl₃) δ 6.84 (s, 2 H), 6.06(s, 1 H), 5.13 (d, 1 H), 4.78 (s, 2 H), 3.33 (s, 3 H), 3.29 (m, 1 H),2.27 (s, 3 H), 2.12 (s, 3 H), 2.04 (s, 6 H), 1.3-1.6 (m, 4 H), 0.93 (t,6 H) ppm.

EXAMPLE 88(1-Ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

To a mixture of(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (80 mg,0.31 mmol) and 2,4,6-trimethylphenol (43 mg, 0.31 mmol) in 2 ml of dryTHF was added potassium tert-butoxide (35 mg, 0.31 mmol) and theresulting mixture was stirred at rt ovemight. The mixture was quenchedwith water and extracted with ethyl acetate. The organic layer was driedand concentrated to give a yellow solid. The solid was purified throughsilica gel column chromatography using 6:4 ratio of chloroform:hexane aseluent to give 91 mg (83%) of the title compound as yellow solid, mp160-162° C. ¹H NMR (CDCl₃) δ 7.62 (d, 1 H), 6.87 (s, 2 H), 6.18 (s, 1H), 3.40 (m,1 H), 2.30 (s, 3 H), 2.15 (s, 3 H), 2.10 (s, 6 H), 1.5-1.8(m, 4 H), 0.99 (t, 6 H) ppm.

EXAMPLE 89N4-(1-Ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine

A mixture of(2-chloro-6-methyl-3-nitro-pyridin-4-yl-(1-ethyl-propylyamine (250 mg,0.97 mmol) and 2,4,6-trimethylaniline (262 mg, 1.94 mmol) in 4 ml of dryDMSO was heated at 130° C. overnight. The mixture was quenched withwater and extracted with ethyl acetate. The organic layer was dried andconcentrated to give a yellow oil. The oil was purified through silicagel column chromatography to give 150 mg (43%) of the title compound asyellow solid, mp 104-107° C. ¹H NMR (CDCl₃) δ 10.36 (s, 1 H), 9.24 (d, 1H), 6.93 (s, 2 H), 5.86 (s, 1 H), 3.45 (m, 1 H), 2.32 (s, 3 H), 2.18 (s,6 H), 2.13 (s, 3 H), 1.55-1.80 (m, 4 H), 0.99 (t, 6 H) ppm.

EXAMPLE 90N4-(1-Ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine

A mixture of(1-ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine(40 mg, 0.112 mmol) and 4 mg of 10% Pd/C in 10 ml of ethanol washydrogenated at 50 psi overnight. The mixture was filtered throughCelite™ and the filtrate was concentrated to dryness to give a lightbrown crystals which were purified through silica gel columnchromatography using 1:1 chloroform:hexane as eluent to give the titlecompound as golden crystals (36 mg, 97%), mp 105-107° C. ¹H NMR (CDCl₃)δ 6.88 (s, 2 H), 6.11 (s, 1 H), 4.00 (brs, 1 H), 3.28 (m, 1 H), 3.10(brs, 2 H), 2.31 (s, 3 H), 2.16 (s, 3 H), 2.10 (s, 6 H), 1.45-1.75 (m, 4H), 0.98 (t, 6 H) ppm. The corresponding HCl salt was prepared as whitesolid, mp 174-178° C., ¹H NMR(D₂O) δ 7.09 (s, 2 H), 6.63 (s, 1 H), 3.65(m, 1 H), 2.31 (s, 3 H), 2.25 (s, 3 H), 2.11 (s, 6 H), 1.45-1.80 (m, 4H), 0.91 (t, 6 H) ppm.

EXAMPLE 91[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-ethyl-propyl)-amine

To a mixture of(2-chloromethyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (850 mg,3.30 mmol) and 4-chloro-2,6-dimethylphenol (516 mg, 3.30 mmol) in 25 mlof dry THF was added potassium tert-butoxide (370 mg, 3.30 mmol) and theresulting mixture was stirred at room temperature overnight. The mixturewas quenched with water and extracted with ethyl acetate. The organiclayer was dried and concentrated to give a yellow solid (1.31 g). Thesolid was purified through silica gel column chromatography using 6:4ratio of chloroform:hexane as eluent to give 1.10 g (88%) of the titlecompound as yellow solid, mp 152-154° C. ¹H NMR (CDCl₃) δ 7.65 (d, 1 H),7.05 (s, 2 H), 6.21 (s, 1 H), 3.41 (m, 1 H), 2.15 (s, 3 H), 2.11 (s, 6H), 1.5-1.8 (m, 4 H), 0.99 (t, 6 H) ppm.

EXAMPLE 922-(2,6-Dimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine

A mixture of(1-ethyl-propyl[6-methyl-3-nitro-2-(4-chloro-2,6-dimethyl-phenoxy)-pyridin-4-yl]-amine(800 mg, 2.12 mmol) and 160 mg of 10% Pd/C in 150 ml of ethanol washydrogenated at 50 psi overnight. The mixture was filtered throughCelite™ and the filtrate was concentrated to dryness to give a purpleglass form (810 mg) which was purified through silica gel columnchromatography using 1:1 chloroform:hexane as eluent to give the titlecompound as tan crystals (360 mg), mp 98-100° C. ¹H NMR (CDCl₃) δ 7.05(m, 3 H), 6.11 (s, 1 H), 4.00 (brs, 1 H), 3.28 (m, 1 H), 3.09 (brs, 2H), 2.14 (s, 9 H), 1.45-1.75 (m, 4 H), 0.98 (t, 6 H) ppm. Thecorresponding HCl salt was prepared as white solid, mp 158-162° C., ¹HNMR(D₂O) δ 7.27 (s, 3 H), 6.67 (s, 1 H), 3.65 (m, 1 H), 2.27 (s, 3 H),2.16 (s, 6 H), 1.45-1.80 (m, 4 H), 0.93 (t, 6 H) ppm.

EXAMPLE 93N4-(1-Ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine

A mixture ofN4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine(40 mg, 0.112 mmol) and 8 mg of 10% palladium/carbon (Pd/C) in 20 ml ofethanol was hydrogenated at 50 psi overnight. The mixture was filteredthrough celite and the filtrate was concentrated to dryness to giveadark residue (40 mg). ¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 5.97 (s, 1 H),4.32 (d, 1 H), 3.28 (m, 1 H),2.27 (s, 3 H), 2.26 (s, 3 H), 2.18 (s, 6H), 1.45-1.75 (m, 4 H), 0.93 (t, 6 H) ppm. The corresponding di-HCl saltwas prepared as a tan solid, mp 213-216° C., ¹H NMR(DMSO-d6) δ 11.1 (s,1 H), 8.48 (s, 1 H), 6.98 (s, 2 H), 6.73 (brs, ¹H), 6.38 (s, 1 H), 3.36(m, 1 H), 2.28 (s, 3 H), 2.19 (s, 3 H), 2.08 (s, 6 H), 1.54 (m, 4 H),0.88 (t, 6 H) ppm.

EXAMPLE 942-(4-Chloro-2,6-dimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine

A mixture of(1-ethyl-propyl)-[6-methyl-3-nitro-2-(4-chloro-2,6-dimethyl-phenoxy)-pyridin-4-yl]-amine(100 mg, 0.265 mmol) and iron (73 mg, 1.33 mmol) in 12 ml of AcOH/H₂O(1:1) was heated at 60° C. for 3 hours. The mixture was concentrated todryness. The residue was diluted with water and extracted with ethylacetate. The organic layer was dried and concentrated to give the titlecompound. ¹H NMR (CDCl₃) δ 7.04 (s, 2 H), 6.12 (s, 1 H), 3.60 (brs, 2H), 3.28 (m, 1 H), 2.14 (s, 3 H), 2.10 (s, 6 H), 1.45-1.80 (m, 4 H),0.97 (t, 6 H) ppm.

EXAMPLE 95N-(1-Ethyl-propyl)-2-methyl-5-nitro-N′-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,6-diamine

To a cooled solution of(6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethyl-pyridin-3-yl)-amine(88 mg, 0.29 mmol) in 1 ml of dry THF was added 1-ethyl-propyl-amine (80mg, 0.92 mmol) at −78° C. The mixture was stirred at that temperaturefor 3 hrs, then warmed to −10° C. for 1 hour. The mixture was quenchedwith water andextracted with ethyl acetate. The organic layer was driedand concentrated to give the title compound (88 mg, 86%) as an orangesolid, mp 151-152° C. ¹H NMR (CDCl₃) δ 9.16 (d, 1 H), 6.92 (s, 1 H),4.35 (m, 1 H), 2.50 (s, 3 H), 2.39 (s, 3 H), 2.18 (s, 3 H), 2.16 (s, 3H), 1.5-1.80 (m, 4 H), 0.94 (t, 6 H) ppm.

EXAMPLE 96(1-Ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-pyrimidin-4-yl]-amine

A solution of 3-hydroxy-2,4,6-trimethylpyridine (41 mg, 0.3 mmol) in 1ml of dry THF was treated with 60% sodium hydride in oil (13 mg, 0.3mmol) at rt. The reaction mixture was cooled to −78° C. and a solutionof (6-chloro-2-methyl-5-nitro-pyrimidin-4-yly(l-ethyl-propylyamine (78mg, 0.3 mmol) in 1 ml of dry THF was added. The reaction was stirred at-78° C for 1 hour, quenched with water and extracted with ethyl acetate.The organic layer was dried and concentrated to give 91 mg (84%) ofwhite solid of the title compound, mp 134-135C. ¹H NMR (CDCl₃) δ 8.30(d, 1 H), 6.89 (s, 2 H), 4.30 (m, 1 H), 2.31 (s, 3 H), 2.26 (s, 3 H),2.10 (s, 6 H), 1.5-1.8 (m, 4 H), 0.97 (t, 6 H) ppm.

EXAMPLE 972-(4-Chloro-2,6-dimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine

A mixture of[2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-ethyl-propyl)-amine(810 mg, 2.14 mmol) and iron (Fe) (594 mg, 10.72 mmol) in 96 ml of 1:1of AcOH:H₂O was heated at reflux for 2 hours. Additional Fe (600 mg) wasadded. The mixture was heated for an additional 1.5 hours. The reactionmixture was concentrated to dryness. The residue was quenched withwater, basified to pH 9.0 and filtered through celite. The filtrate wasextracted with ethyl acetate. The organic layer was washed with brine,dried and concentrated to give the title compound as a yellow oil. Theoil was purified through silica gel column chromatography usingchloroform as eluent to give 570 mg of2-(4chloro-2,6-dimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine as a tan solid, mp72-74° C. ¹H NMR(CDCl₃) δ 7.04(s,2 H), 6.11(s,1 H), 4.03(d,1 H),3.30(m,1 H), 3.07(s,1 H), 2.14(s,3 H), 2.10(s,6 H), 1.4-1.75(m,4 H),0.97(t,6 H)ppm. The corresponding di-HCl salt was prepared as a whitesolid, mp 208-210° C.

EXAMPLE 98N-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide

A mixture of2-(2,4,6-trimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3,4-diamine(250 mg, 0.763 mmol), acetic anhydride (72 mg, 0.763 mmol) andtriethylamine (77 mg, 0.763 mmol) in 5 ml of methylene chloride wasstirred at room temperature for 3 hours. The mixture was quenched withwater and extracted with ethyl acetate. The organic layer was dried andconcentrated to dryness to give 310 mg of the crude material. The crudematerial was purified through silica gel column chromatography using 2%methanol in chloroform as eluent to give 250 mg (89% yield) ofN-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamideas tan solid, mp 154-156° C. ¹H NMR(CDCl₃) δ 6.97(0.64 H), 6.86(s,2 H),6.26(0.36 H), 6.14(o.64 H), 6.12(s,0.36 H), 4.80(d,0.64 H), 4.40(d,0.36H), 3.2-3.4(m,1 H), 2.29(s,3 H), 2.26(s,1.9 H), 2.17(s,1.1 H),2.16(s,1.9 H), 2.06(s,6 H), 1.99(s,1.1 H), 1.4-1.75(m,4 H), 0.97(t,6H)ppm.

EXAMPLE 99N-[2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-acetamide

The title compound (35 mg) was isolated as a side product from thereduction experiment described in the Example 97. Compound can beprepared by standard acylation method by reacting2-(4-chloro-2,6-dimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyi-pyridine-3,4-diaminewith acetic anhydride and triethylamine in methylene chloride. A tansolid was prepared, mp 161-164° C. ¹H NMR(CDCl₃) δ 7.04(s,2 H),6.88(s,0.6 H), 6.26(s,0.4 H), 6.15(s,1 H), 4.75(d,0.6 H), 4.40(d,0.4 H),3.30(m,1 H), 2.27(s,1.8 H), 2.15(s,3 H), 2.06(s,6 H), 1.98(s,1.2 H),1.4-1.8(m,4 H), 0.97(t,6 H)ppm.

EXAMPLE 1001-Ethyl-3-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-urea

¹H NMR(CDCl₃) δ 6.85(s,2 H), 6.11(s,1 H), 5.38(s,1 H), 4.68(s,1 H),4.65(m,1 H), 3.2-3.4(m,3 H), 2.28(s,3 H), 2.16(s,3 H), 2.08(s,6 H),1.4-1.7(m,4 H), 1.10(t,3 H), 0.93(t,6 H)ppm.

EXAMPLE 101N-[4-Ethyl-propyl)-2-methyl-N″-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,5,6-triamine

The title compound was prepared by hydrogenation ofN-(1-ethyl-propyl)-2-methyl-5-nitro-N″-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,6-diamine by the methodanalogous to that described in Example 93. ¹H NMR(CDCl₃) δ 6.9(s,1 H),6.25(brs,1 H), 4.7(d,1 H), 4.08(m,1 H), 2.5(s,3 H), 2.45(s,3 H),2.30(s,3 H), 2.20(s,3 H), 1.45-1.7(m,4 H), 0.98(t,6 H) ppm.

EXAMPLE 102N4-(1-Ethyl-propyl)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine-4,5-diamine

The title compound was prepared by hydrogenation of(1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl]-amine by the method analogous tothat described in Example 93. ¹H NMR(CDCl₃) δ 6.88(s,2 H), 4.52(d,1 H),4.10(m,1 H), 2.94(brs,2 H), 2.30(s,3 H), 2.23(s,3 H), 2.09(s,6 H),1.4-1.8(m,4 H), 0.95(t,6 H) ppm. The corresponding HCl salt, mp 248-250°C. ¹H NMR(CD₃OD) δ 6.91(s,2 H), 4.00(m,1 H), 2.39(s,3 H), 2.28(s,3 H),2.07(s,6 H), 1.6-1.8(m,4 H), 1.00(t,6 H) ppm.

EXAMPLE 103[6-(1-Ethyl-propoxy)-2-methyl-5-nitro-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine

A mixture of 3-pentanol (0.5 ml) and 60% sodium hydride (NaH) in oil (89mg, 2.22 mmol) in 2 ml of dry THF was stirred for 2 min, then treatedwith a solution of6-(chloro-2-methyl-5-nitropyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine(350 mg, 1.14 mmol) in 3 ml of dry THF at −78° C. and stirred at thattemperature for 1 hour, then stirred at room temperature overnight. Themixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried and concentrated to give the crude materialwhich was purified through silica gel column chromatography using 2:1 ofhexane/CHCl₃ as eluent to give 331 mg (85%) of the title compound as ayellow solid, mp 112-113° C. ¹H NMR(CDCl₃) δ 9.48(brs,1 H), 6.49(s,2 H),5.37(m,1 H), 2.33(s,3 H), 2.29(s,3 H), 2.18(s,6 H), 1.7-1.9(m,4 H),0.99(t,6 H) ppm.

EXAMPLE 104N-(1-Ethyl-propyl)-2-methyl-5-nitro-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine

The title compound was prepared by the method analogous to thatdescribed in Example 5 using 1-ethylpropylamine. ¹H NMR(CDCl₃) δ10.48(s,1 H), 9.25(d,1 H), 6.94(s,2 H), 4.37(m,1 H), 2.32(s,3 H),2.21(s,3 H), 2.18(s,6 H), 1.5-1.8(m,4 H), 0.97(t,6 H) ppm.

EXAMPLE 1056-(1-Ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine

The title compound was prepared by the method analogous to thatdescribed in Example 93 starting from[6-(1-ethyl-propoxy)-2-methyl-5-nitro-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine.¹H NMR(CDCl₃) δ 6.92(s,2 H), 5.96(s,1 H), 5.12(m,1 H), 2.85(brs,1 H),2.31(s,3 H), 2.30(s,3 H), 2.19(s,6 H), 1.70(m,4 H), 0.94(t,6 H) ppm.

EXAMPLE 1066-(1-Ethyl-propoxy)-2-methyl-5-nitro-pyrimidin-4-yl]-(2,4,6-trimethyl-pyridin-3-yl)-amine

The title compound was prepared by the method analogous to thatdescribed in Example 103 starting from(6-chloro-2-methyl-5-nitropyrimidin-4-yl)-(2,4,6-trimethyl-pyridin-3-yl)-amineand sodium 3-pentanoxide. ¹H NMR(CDCl₃) δ 9.45(s,1 H), 6.95(s,1 H),5.35(m,1 H), 2.53(s,3 H), 2.41(s,3 H), 2.29(s,3 H), 2.18(s,3H),1.7-1.9(m,4 H), 0.98(t,6 H) ppm.

EXAMPLE 107N-(1-Ethyl-propyl)-2-methyl-N″-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5,6-triamine

The title compound was prepared by the method analogous to thatdescribed in Example 93 starting fromN-(1-ethyl-propyl)-2-methyl-5-nitro-N′-(2,4,6-trimethyl-phenylpyrimidine-4,6-diamine.¹H NMR(CDCl₃) δ 6.90(s,2 H), 6.10(s,1 H), 4.78(d,1 H), 4.03(m,1 H),2.31(s,3 H), 2.29(s,3 H), 2.20(s,6 H), 1.4-1.6(m,4 H), 0.91 (t,6 H) ppm.

EXAMPLE 1086-(1-Ethyl-propoxy)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-6-one

A mixture of6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine(182 mg, 0.554 mmol), triethylamine (39 mg, 0.388 mmol) and triphosgene(58 mg, 0.196 mmol) in 6 ml of dry THF was stirred at room temperaturefor 30 min. The mixture was quenched with water and extracted withchloroform. The organic layer was dried and concentrated to give 177 mg(90%) of the title compound as a white solid, mp 159-160° C. ¹HNMR(CDCl₃) δ 8.50(s,1 H), 6.99(s,2 H), 5.30(m,1 H), 2.47(s,3 H),2.32(s,3 H), 2.08(s,6 H), 1.73(m,4 H), 0.94(t,6 H) ppm.

EXAMPLE 1096-(1-Ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,5-diamine

The title compound was prepared by the method analogous to thatdescribed in Example 93 starting from6-(1-ethyl-propoxy)-2-methyl-5-nitro-pyrimidin-4-yl]-(2,4,6-trimethyl-pyridin-3-yl)-amine.¹H NMR(CDCl₃) δ 6.89(s,1 H), 5.97(s,1 H), 5.29(m,1 H), 2.90(brs,1 H),2.48(s,3 H), 2.41(s,3 H), 2.26(s,3 H), 2.17(s,3 H), 1.68(m,4 H),0.93(t,6 H)popm.

EXAMPLE 1106-(1-Ethyl-propylamino)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one

The title compound was prepared by the method analogous to thatdescribed in Example 108 starting fromN-(1-ethyl-propyl)-2-methyl-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5,6-triamine.¹H NMR(CDCl₃) δ 6.59(s,2 H), 5.28(d,1 H), 3.92(m,1 H), 2.40(s,3 H),2.32(s,3 H), 2.08(s,6 H), 1.25-1.45(m,4 H), 0.80(t,6 H)ppm.

EXAMPLE 111

N4-(1-Ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamineandN4-(1-Ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine

To a solution ofN4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine(0.250 g, 0.763 mmol) in dry THF (6 ml) was treated with 1M LiN(SiMe₃)₂in THF (1.0 ml, 1.0 mmol) at −78° C. and stirred for 10 min. an excessof methyl iodide was added and the resulting mixture was stirred at roomtemperature overnight. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was dried and concentrated to givea crude material. The crude material was purified through silica gelcolumn chromatography using 5% ethyl acetate in hexane as eluent to giveN4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine andN4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine.

N4-(1-Ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine:¹H NMR(CDCl₃) δ 6.88(s,2 H), 6.02(s,1 H), 5.55(d,1 H), 3.21(m,1 H),2.79(s,6 H), 2.30(s,3 H), 2.10(s,3 H), 2.09(s,6 H), 1.4-1.75(m,4 H),0.95(t,6 H) ppm.

N4-(1-Ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine:¹H NMR(CDCl₃) δ 6.89(s,2 H), 6.10(s,1 H), 4.84(d,1 H), 3.30(m,1 H),2.98(s,1 H), 2.72(s,3 H), 2.32(s,3 H), 2.16(s,3 H), 2.12(s,6 H),1.45-1.70(m,4 H), 0.99(t,6 H) ppm.

EXAMPLE 112N4-(1-Ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyrimidine-3chloro-4-amine

The title compound was prepared by the method analogous to those ofExamples 33-39 starting from3,4-dichloro-6methyl-2-(2,4,6-trimethyl-phenoxy)-pyrimidine and1-ethyl-propylamine. ¹H NMR(CDCl₃) δ 6.87(s,2 H), 4.97(d,1 H), 4.12(m,1H), 2.30(s,3 H), 2.25(s,3 H), 2.10(s,6 H), 1.4-1.8(m,4 H), 0.96(t,6 H)ppm.

EXAMPLE 113Butyl-(2,8-dimethyl-9-(2,4,6-trimethyl-phenyl)-9H-purin-6-yl)-ethyl-amine

A mixture ofN-butyl-N-ethyl-2-methyl-N′-(2,4,6-trimethylphenyl)-pyrimidine-4,5,6-triamine (105 mg, 0.63 mmol) and triethyl orthoacetate (0.204 g,1.25mmol) and 10 mg of p-TsOH in toluene was heated reflux overnight. Themixture was concentrated to dryness and the residue was quenched withwater and extracted with ethyl acetate. The organic layer was dried andconcentrated to give yellow oil. The oil was purified through silica gelcolumn chromatography using 1:1 of hexane:chloroform as eluent to givethe title compound. ¹H NMR(CDCl₃) δ 7.01(s,2 H), 3.9-4.1(m,4 H),2.45(s,3 H), 2.35(s,3 H), 2.20(s,3 H), 1.91(s,6 H), 1.6-1.8(m,2 H),1.35-1.5(m,2 H), 1.29(t,3 H), 0.99(t,3 H) ppm.

EXAMPLE 114

The compounds below were prepared by reacting of(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(alkyl- or dialkyl)-amine withsubstituted phenol by a method analogous to the following: To a mixtureof (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(alkyl- or dialkyl)-amine (1mmol) and 2,4,6-trimethylphenol (1 mmol) in dry THF was added potassiumtert-butoxide (1 mmol) and the resulting mixture was stirred at roomtemperature until all starting material was consumed. The mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas dried and concentrated to give the title compound after purificationthrough silica gel column chromatography:

2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.69(,1 H), 6.289s,1 H), 3.65-3.80(m,2 H), 3.60(m,1 H),2.12(s,3 H), 2.08(s,6 H), 1.8(brs,1 H), 1.5-1.8(m,2 H), 1.01(t,3 H) ppm.

(1-Methoxymethyl-propyl)-[6-methyl-3-nitro-2-(4-trifluoromethoxy-phenoxy)pyridin-4-yl]-amine

yellow solid, mp. 75-76° C., Anal. For C₁₈H₂₀N₃O₅F₃, calc. C52.05; H,4.85; N, 10.12; found, C, 52.14; H, 5.04; N, 10.13

2-(2-Amino-4,6-dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR (CDCl₃) d 9.55(d,1 H), 7.23(d,1 H), 7.00(d,1 H), 6.05(s,1 H),3.69(m,1 H), 3.49(m,2 H), 3.38(s,3 H), 2.35(s,3 H), 1.78(m,1 H),1.65(m,1 H), 0.99(t,3 H) ppm.

3-Methoxy-2-[4-(1-methoxymethyl-propylamino)-6-methyl-3-nitro-pyridin-2-yloxy]-benzaldehyde

yellow solid, mp. 126.5-130.5° C., Anal. For C₁₉H₂₃N₃O₆, calc. C58.60;H, 5.95; N, 10.79; found, C, 58.45; H, 6.11; N, 10.32

[2-(2,6-Dibromo-4-trifluoromethoxy-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1 -methoxymethyl-propyl)-amine

yellow solid, 1H NMR(CDCl₃) d 8.00(d,1 H), 7.49(,2 H), 6.35(s,1 H),3.64(m,1 H), 3.53(m,2 H), 3.43(s,3 H), 2.20(s,3 H), 1.6-1.9(m,4 H),1.04(t,3 H)ppm.

[2-(2-Bromo-4-chloro-6-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

yellow solid, mp. 111.8-113.6° C., Anal. For C₁₅H₂₁N₃O₅BrCl, calc, C,45.54; H, 4.46; N, 8.85; found, C, 45.94; H, 4.32; N, 8.68

[2-(2,4-Dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR (CDCl₃) d 7.183(d,1 H), 7.46(d,1 H), 7.30(dd,1 H), 7.15(dd,1 H),6.33(s,1 H), 3.65(m,1 H), 3.51(m,2 H), 3.42(s,3 H), 2.21(s,3 H),1.82(m,1 H), 1.66(m,1 H), 1.03(t,3 H) ppm.

[2-(2-Bromo-6-chloro-4-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 7.88(d,1 H), 7.04(d,1 H), 6.93(d,1 H), 6.27(s,1 H),3.79(s,3 H), 3.60(m,1 H), 3.4-3.5(m,2 H), 3.38(s,3 H), 2.15(s,3 H),1.78(m,1 H), 1.64(m,1 H), 0.99(t,3 H)

(1-Methoxymethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine

mp. 126.8-129.5° C.; Anal. For C₂₀H₂₇N₃O₇ calc. C, 57.00; H, 6.46; N,9.97; found C, 56.94; H, 6.85; N, 9.66.

EXAMPLE 1152-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide

To a solution ofN4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine(250 mg, 0.763 mmol) in dry THF was added chloroacetyl chloride (86 mg,0.763 mmol) and triethylamine (77 mg, 0.763 mmol) at 0° C. The resultingmixture was warmed to room temperature and stirred for 1 hr. The mixturewas quenched with water and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give the title compound as a solid. The solidwas purified through silica gel column chromatography to give 280mg(91%) of tan crystals, mp. 152-154° C.

1H NMR(CDCl₃) d 8.07(brs,1 H), 6.88(s,2 H), 6.16(s,1 H), 4.75(m,1 H),4.25(s,2 H), 3.33(m,1 H), 2.30(s,3 H), 2.18(s,3 H), 2.08(s,6 H),1.4-1.75(m,4 H), 0.97(t,6 H) ppm.

The following compounds were prepared by an analogous method to that inthe preceding paragraph:

3-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-propionamide

tan solid,mp. 183-185° C. Anal. For C₂₃H₃₂ClN₃O₂ calc, C, 66.09; H,7.72; N, 10.05; found, C, 66.27; H, 7.87; N, 9.99.

2-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-propionamide

mp. 170-172° C., Anal. For C₂₃H₃₂ClN₃O₂ calc. C, 66.09; H, 7.72; N,10.05; found C, 66.20; H, 7.52; N, 10.09.

EXAMPLE 116N3-Allyl-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine

To a solution ofN4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine(500 mg, 1.52 mmol) in dry THF was added 1 M in THF of lithiumbis(trimethylsilyl)amide (1.6 ml, 1.6 mmol) at −78° C., After stirringat −78° C. for 10 min, allyl bromide (0.13 ml, 1.52 mmol) was added andthe resulting mixture was stirred at that temperature for 20 min, thenwarmed to room temperature overnight. The mixture was quenched withwater and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated to dryness to givethe title compound as a green-blue oil. The oil was purified throughsilica gel column chromatography using 5% ethyl acetate in hexane aseluent to give a yellow crystal, mp. 86-88° C.

1H NMR(CDCl₃) d 6.87(s,2 H), 6.0(m,2 H), 5.2-5.35(m,2 H), 4.8(d,1 H),3.54(d,2 H), 3.3(m,1 H), 3.05(s,1 H), 2.30(s,3 H), 2.14(s,3 H), 2.09(s,6H), 1.4-1.6(m,4 H), 0.96(t,6 H) ppm.

The following compounds were prepared by an analogous method:

N3-(3-Chloro-propyl)-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine

1H NMR(CDCl₃) d 6.85(s,2 H), 6.05(s,1 H), 4.9(d,1 H), 3.8(m,2 H),3.3(m,1 H), 3.1(m,2 H), 2.3(s,3 H), 2.159s,3 H), 2.04(s,6 H), 1.79m,2H), 1.5(m,2 H), 1.0(m,6 H) ppm.

N4-(1-Ethyl-propyl)-6-methyl-N3-propa-1,2-dienyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine

1H NMR(CDCl₃) d 8.93(d,1 H), 6.86(s,2 H), 6.66(m,1 H), 6.09(s,1 H),5.4-5.6(m,2 H), 5.54(d,1 H), 3.27(m,1 H), 2.27(s,3 H), 2.12(s,3 H),2.05(s,6 H), 1.6(m,4 H), 0.94(t,6 H) ppm.

EXAMPLE 1172-[3-Amino-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

A mixture of2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-(S)-ylamino]-butan-1-ol(120 mg) and Fe (73 mg) in 12 ml of 1:1 of AcOH:H2O was heated at refluxfor 2 hr. The reaction mixture was to dryness. The residue was quenchedwith water, basified to pH 12 and filtered through celite. The filtratewas extracted with chloroform. The organic layer was washed with brine,dried and concentrated to give the title compound as a yellow solid. Thesolid was purified through silica gel column chromatography using 1:1EtOAc:hexane as eluent to give the title compound as a white solid, mp.161-162° C.

1H NMR(CDCl₃) d 7.03(s,2 H), 6.15(s,1 H), 3.75(m,2 H), 3.47(m,1 H),2.25(brs,3 H), 2.08(s,6 H), 1.5-1.8(m,2 H), 0.98t,3 H) ppm

EXAMPLE 1182-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

A mixture of4chloro-6-methyl-2-(4-Chloro-2,6-dimethyl-phenoxy)-nicotinic acid methylester (77 mg, 0.226 mmol) and 1-ethyl-propyl-amine in DMSO was heated at120° C. for 4 hr. The mixture was quenched with sat. ammonium chloride,water, brine and extracted with ethyl acetate. The organic layer wasdried and concentrated to give 140 mg of yellow solid. 1HNMR(CDCl₃) d8.10(d,1 H), 7.03(s,2 H), 6.09(s,1 H), 3.88(s,3 H), 3.35(m,1 H),2.10(s,3 H), 2.08(s,6 H), 1.5-1.7(m,4 H), 0.96(t,6 H) ppm.

EXAMPLE 1192-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

A mixture of4-chloro-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-nicotinic acid methylester and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 16 hr.The mixture was quenched with water, brine and extracted with ethylacetate. The organic layer was dried and concentrated to dryness. Theresidue was purified through silica gel column chromatography usinghexane to 3% ethyl acetate in hexane as eluent to give the titlecompound as a white solid. 1H NMR(CDCl₃) d 8.1(d,1 H), 7.18(s,2 H),6.08(s,1 H), 3.87(s,3 H), 3.35(m,1 H), 2.10(s,3 H), 2.08(s,6 H),1.4-1.7(m,4 H), 0.96(t,6 H) ppm.

EXAMPLE 1204-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester and 1-ethyl-propyl-amine in DMSO was heated at 130° C.overnight. The mixture was quenched with water, brine and extracted withethyl acetate. The organic layer was dried and concentrated to dryness.The residue was purified through silica gel column chromatography togive the title compound. 1H NMR(CDCl₃) d 8.26(d,1 H), 6.87(s,2 H),6.26(s,1 H), 4.11(m,1 H), 3.87(s,3 H), 2.324(m, 1 H), 2.30(s,3 H),2.17s,3 H), 2.08(s,6 H), 1.92(q,2 H), 1.16(t,3 H) ppm.

EXAMPLE 1214-(s)-(1-Hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

A mixture of 4-chloro-2-(2,4,6-trimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester (500 mg, 1.56 mmol) and (S)-2-amino-1-butanol (696 mg,7.82 mmol) in DMSO was heated in 130° C. oil bath for 24 hr. The mixturecooled to rt and quenched with water and extracted with ethyl acetate.The organic layer was separated, washed with water, dried over anhydroussodium sulfate, filtered, and concentrated to dryness to give 610 mg ofcrude product as an oil. The oil was purified through silica gel columnchromatography using 30% ethyl acetate in hexane as eluent to give thetitle compound. Anal. calc. for C₂₁H₂₈N₂O₄. ½H₂O: C, 66.11; H, 7.66; N,7.34; found: C, 66.27; H, 7.60; N, 7.21.

EXAMPLE 1224-(1-Ethyl-2-hydroxy-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

A mixture of 4-chloro-2-(2,4,6-trimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester (250 mg, 0.78 mmol) and 3-amino-pentan-2-ol (320 mg,3.13 mmol) in DMSO was heated in 130° C. oil bath for 24 hr. The mixturecooled to rt and quenched with water and extracted with ethyl acetate.The organic layer was separated, washed with water, dried over anhydroussodium sulfate, filtered, and concentrated to dryness to give 280 mg ofcrude product as an oil. The oil was purified through silica gel columnchromatography using 20% ethyl acetate in hexane as eluent to give thetitle compound as a yellow solid, mp 116-120° C.

1H NMR(CDCl3) d 8.17(m,1 H), 6.87(s,2 H), 6.21&6.14(two s, 1 H),3.88(s,3 H), 3.8-4.0(m,2 H), 3.5(m,1 H), 3.3(m,1 H), 2.30(s,3 H),2.12(s,3 H), 2.09(s,6 H), 1.8(d,1 H), 1.5-1.8(m,2 H), 1.26(d,3 H),0.99(t,3 H) ppm.

EXAMPLE 1232-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

A mixture of4-chloro-2-(4-bromo-2,6-trimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester (850 mg) and (S)-2-amino-1-butanol in DMSO was heated in130° C. oil bath for 24 hr. The mixture cooled to rt and quenched withwater and extracted with ethyl acetate. The organic layer was separated,washed with water, dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give 764 mg of crude product as an oil. Theoil was purified through silica gel column chromatography to give thetitle compound. 1H NMR (CDCl₃) d 8.15(d,1 H), 7.16(s,2 H), 6.18(s,1 H),3.86(s,3 H), 3.72(m,1 H), 3.70(m,1 H), 3.54(m,1 H), 2.10(s,3 H),2.06(s,6 H), 1.5-1.8(m,2 H), 1.00(t,3 H) ppm.

EXAMPLE 1242-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

A mixture of4-chloro-2-(4-bromo-2,6-trimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester and 1-methoxymethyl-propylamine in DMSO was heated in 130°C. oil bath for 24 hr. The mixture cooled to rt and quenched with waterand extracted with ethyl acetate. The organic layer was separated,washed with water, dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give crude product. The cude compound waspurified through silica gel column chromatography to give the titlecompound.

EXAMPLE 1252-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

A mixture of4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester (9.000 g, 26.45 mmol) and (S)-2-amino-1-butanol (12.7 ml)in 1-methyl-2-pyrrolidinone was heated at 130° C. for 2 hr, then at 100°C. overnight. The mixture cooled to rt and poured into ice-water anddiluted with ethyl acetate. The organic layer was separated, washed withwater, dried over anhydrous sodium sulfate, filtered, and concentratedto dryness to give 13.6 g of crude product as a light yellow oil. Theoil was purified through silica gel column chromatography usingchloroform to 2% MeOH in chloroform as eluent to give 6.6839 g (64%) ofthe title compound as a white glass foam. The glass foam was trituratedwith hexane to give a white solid. The solid was recrystallized fromdi-iso-propyl ether to give a white crystals, mp 122.5-124° C. Anal.calc. for C₂₀H₂₅ClN₂O₄: C, 61.14; H, 6.41; N, 7.13; found: C, 60.98; H,6.43; N, 6.95.

EXAMPLE 1262-(4-Chloro-2-methoxy-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

A mixture of 4-chloro-2-(4-Chloro-2-methoxy-phenoxy)-6-methyl-nicotinicacid methyl ester and (S)-2-amino-1-butanol in 1-methyl-2-pyrrolidinonewas heated at 130° C. overnight. The mixture cooled to room temperatureand poured into ice-water and diluted with ethyl acetate. The organiclayer was separated, washed with water, dried over anhydrous sodiumsulfate, filtered, and concentrated to dryness. The residue was purifiedthrough silica gel column chromatography to give the title compound as asolid mp. 92.8-93.8° C., Anal. For C₁₉H₂₃N₂O₅Cl calc. C, 57.80; H, 5.87;7.09; found, C, 57.70; H, 5.89; 7.02.

EXAMPLE 1272-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinicacid methyl ester

A mixture of4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester (500 mg, 1.47 mmol) and 3-amino-pentan-2-ol (758 mg, 7.35mmol) in 1-methyl-2-pyrrolidinone was heated in 130° C. oil bath for 24hr. The mixture cooled to rt and quenched with water and extracted withethyl acetate. The organic layer was separated, washed with water, driedover anhydrous sodium sulfate, filtered, and concentrated to dryness togive an oil. The oil was purified through silica gel columnchromatography using 20% ethyl acetate in hexane as eluent to give thetitle compound as a white crystal, mp 133-135° C.

1H NMR(CDCl₃) d 8.19(m,1 H), 7.00(s,2 H), 6.20&6.14(two sets of s,1 H),3.8-3.9(m,1 H), 3.86(s,3 H), 3.3&3.5(two sets of m,1 H), 2.07(s,3 H),2.06(s,6 H), 1.75(m,1 H), 1.55(m,1 H), 1.24(d,3 H), 0.96(t,3 H)ppm.

EXAMPLE 1282-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6-methyl-nicotinicacid methyl ester

To a solution of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinicacid methyl ester (50 mg, 0.123 mmol) in dry THF was added NaH andstirred for 20 min. An excess of MeI was added and the resulting mixturewas stirred at rt overnight. The mixture cooled to rt and quenched withwater and extracted with ethyl acetate. The organic layer was separated,washed with water, dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give an oil. The oil was purified throughsilica gel column chromatography using 20% ethyl acetate in hexane asaneluent to give the title compound as a clear oil. 1H NMR(CDCl3) d8.20(d,1 H), 7.00(s,2 H), 6.14&6.10(two sets of s,1 H), 3.859s,3 H),3.47(m,1 H), 3.39&3.37(two sets of s,3 H), 2.08(s,3 H), 2.06(s,6 H),1.75(m,1 H), 1.58(m,1 H), 1.14(t,3 H), 0.95(t,3 H)ppm.

EXAMPLE 1292-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinicacid methyl ester

The title compound was prepared by Dess-Martin oxidation of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinicacid methyl ester. A white solid was obtained after silica gel columnchromatography. 1H NMR(CDCl₃) d 8.6(d,1 H), 7.01(s,2 H), 5.899s,1 H),3.9-4.0(m,1 H), 3.90(s,3 H), 2.17(s,3 H), 2.07(s,3 H), 2.05(s,3 H),1.859m,1 H), 1.93(m, 1 H), 1.00(t,3 H) ppm.

EXAMPLE 1302-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinicacid methyl ester

The title compound was prepared by Dess-Martin oxidation of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester. The title compound was obtained after columnchromatography. 1H NMR (CDCl3) 9.54(d,1 H), 8.56(d,1 H), 7.01(s,2 H),5.93(s,1 H), 3.92(m,1 H), 3.89(s,3 H), 2.08(s,3 H), 2.05(s,6 H),1.05(t,3 H) ppm.

EXAMPLE 1312-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-yl)-6-methyl-nicotinicacid methyl ester

A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester (106 mg, 0.27 mmol) , triphosgene )27 mg, 0.090 mmol),triethylamine (27 mg, 0.27 mmol) in dry THF was stirred at roomtemperature for 2 hr. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was separated, washed with water,dried over anhydrous sodium sulfate, filtered, and concentrated todryness to give 13.6 g of crude product as a white glass foam. The foamwas triturated with hexane/diethyl ether to give a white solid, mp.144-145.5° C., Anal. For C₂₁H₂₃ClN₂O₅ calc.: C, 60.22; H, 5.53; N, 6.69;found: C, 60.10, H, 5.79; N, 6.66.

EXAMPLE 1322-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-[(2-hydroxy-ethylamino)-methyl]-propylamino)-6-methyl-nicotinicacid methyl ester

To a solution of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinicacid methyl ester in dichloroethane was added 2-amino-ethanol, sodiumcyanoborohydride, acetic acid, anhydrous sodium sulfate. The resultingmixture was heated at reflux and cooled to rt. The mixture was quenchedwith water and extracted with chloroform. The organic layer wasseparated, washed with water, dried over anhydrous sodium sulfate,filtered, and concentrated to dryness. After chromatography, the titlecompound was obtained as a white glass foam. 1H NMR(CDCl₃) d 8.3(d,1 H),7.0(s,2 H), 6.1(s,1 H), 3.9(s,3 H), 3.64(m,2 H), 3.57(m,1 H), 2.90(m,2H), 2.83(m,2 H), 2.5(brs,2 H), 2.09(s,3 H), 2.06(s,6 H), 1.65(m,2 H),0.97(t,3 H) ppm.

EXAMPLE 1334-[Ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester and 1-ethyl-propyl-amine in 1-methyl-2-pyrrolidinonewas heated at 130° C. until starting material was consumed. The mixturewas quenched with water, brine and extracted with ethyl acetate. Theorganic layer was dried and concentrated to dryness. The residue waspurified through silica gel column chromatography to give the titlecompound. 1H NMR(CDCl₃) d 6.85(s,2 H), 6.40(s,1 H), 3.88(s,3 H),3.73(t,2 H), 3.43(t,2 H), 3.31(q,2 H), 2.27(s,3 H), 2.22(s,3 H),2.06(s,6 H), 1.15(t,3 H) ppm.

EXAMPLE 1344-[Ethyl-(2-methanesulfonyloxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

A mixture of4-[ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester, methanesulfonyl chloride and triethylamine inmethylene chloride was stirred at rt until all starting material wereconsumed. The mixture was quenched with water, brine and extracted withmethylene chloride. The organic layer was dried and concentrated todryness. The residue was purified through silica gel columnchromatography to give the title compound. 1H NMR(CDCl₃) d 6.83(s,2 H),6.25(s,1 H), 4.34(t,2 H), 3.86(s,3 H), 3.6(t,2 H), 3.38(t,2 H), 3.09s,3H), 2.25(s,3 H), 2.20(s,3 H), 2.04(s,6 H), 1.18(t,3 H) ppm.

EXAMPLE 1354-[(2-Hydroxy-ethyl)-thiophen-2-ylmethyl-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester and 2-[(thiophen-2-ylmethyl)-amino]-ethanol in1-methyl-2-pyrrolidinone was heated at 130° C. overnight. The mixturewas quenched with water, brine and extracted with ethyl acetate. Theorganic layer was dried and concentrated to dryness. The residue waspurified through silica gel column chromatography to give the titlecompound. 1H NMR (CDCl₃) d 7.22(m,1 H), 6.94m,2 H), 6.84(s,2 H),6.44(s,1 H), 4.52(s,2 H), 3.91(s,3 H), 3.679t,2 H), 3.369t,2 H),2.279s,3 H), 2.20(s,3 H), 2.07(s,6 H) ppm.

EXAMPLE 136

The following compounds were prepared by the method analogous to that inExample 118, starting with an appropriate4-chloro-6-methyl-2-(substituted-phenoxy)-nicotinic acid alkyl esterwith an appropriate alkyl- or dialkyl-amine.

4-(2,2-Dimethyl-4-phenyl-[1,3]dioxan-5-ylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

1H NMR (CDCl₃) d 8.71(d,2 H), 7.1-7.4(m,5 H), 6.82(s,2 H), 5.55(s,1 H),5.229s,1 H), 4.29(d,1 H), 3.97(d,1 H), 3.869s,3 H), 3.61(d,1 H),2.25(s,3 H), 2.01(s,6 H), 1.91(s,3 H), 1.65(s,3 H), 1.61 (s,3 H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid ethyl ester

1H NMR(CDCl₃) d 8.01(d,1 H), 7.02(s,2 H), 6.17(s,1 H), 4.33(q,2 H),3.71(m,1 H), 3.66(m,1 H), 3.54m,1 H), 2.10(s,3 H), 2.07(s,6 H),1.5-1.8(m,2 H), 1.33(t,3 H), 1.00(t,3 H) ppm.

4-[Ethyl-(2-methoxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

1H NMR(CDCl₃) d 6.83(s,2 H), 6.19(s,1 H), 3.869s,3 H), 3.35-3.6(m,4 H),3.35(s,3 H), 2.26(s,3 H), 2.15(s,3 H), 2.06(s,6 H), 1.179t,3 H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S,R)-&(S,S)-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.2(d,1 H), 7.01(s2 H), 6.20(s, 0.2 H), 6.15(s,0.8 H),3.92(m,1 H), 3.87(s,3 H), 3.48(m,0.2 H), 3.31 (m,0.8 H), 2.08(s,3 H),2.06(s,6 H), 1.5-1.8(m,2 H), 1.25(d,3 H), 0.96(t,3 H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(R)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

1H NMR(CDCl₃) 8.12(d,1H), 7.00(s,2 H), 6.16(s,1 H), 3.85(s,3 H),3.6-3.8(m,2 H), 3.53(m,1 H), 2.08(s,3 H), 2.05(s,6 H), 1.5-1.8(m,2 H),0.98(t,3 H)ppm.

4-(2-Hydroxy-1-hydroxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.44(d,1 H), 6.84(s,2 H), 6.17(s,1 H), 3.8-4.0(m,4 H),3.85(s,3 H), 3.70(m,1 H), 2.60(s,3 H), 2.27(s,3 H), 2.11(s,2 H),2.05(s,6 H) ppm.

4-(2-Methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.38(d,1 H), 6.88(s,2 H), 6.18(s,1 H), 3.88(s,3 H),3.78(m,1 H), 3.56(m,2 H), 3.44(s,6 H), 2.31(s,3 H), 2.15(s,3 H),2.09(s,6 H) ppm.

4-(1-Hydroxymethyl-2-methoxy-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.44(d,1 H), 6.88(s,2 H), 6.21(s,1 H), 3.89(s,3 H),3.80(m,1 H), 3.5-3.7(m,2 H), 3.45(s,3 H), 2.31(s,3 H), 2.16(s,3 H),2.09(s,6 H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-butylamino)-6-methyl-nicotinicacid methyl ester

1H NMR (CDCl₃) d 8.34(d,1 H), 7.069s,2 H), 6.16(s,1 H), 3.91(s,3 H),3.70(m,1 H), 3.5(m,1 H), 2.13(s,3 H), 2.11(s,6 H), 1.5-1.9(m,4 H),1.01(m,6 H) ppm.

EXAMPLE 137[2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol

A mixture of4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester (130 mg, 0.332 mmol) and an excess of 1 M diisobutylaluminum hydride in THF in dry THF was stirred at −78° C. for 10 min,then warmed to rt. The mixture was quenched with methanol and stirred atroom temperature for 20 min, filtered through celite and washed withmethanol and chloroform. The filtrate was concentrated to dryness. Theresidue was purified through silica gel column chromatography to. givethe title compound. 1HNMR(CDCl₃) d 7.03(s,2 H), 6.11(s,1 H), 5.03(d,1H), 4.96(s,2 H), 3.32(m,1 H), 2.14(s,3 H), 2.07(s,6 H), 1.4-1.7(m,4 H),0.96(t,6 H) ppm.

[2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol

The title compound was prepared by the method analogous to that in thepreceding paragraph. 1H NMR(CDCl₃) d 7.18(s,2 H), 6.11(s,1 H), 5.05(d,1H), 4.91(d,2 H), 3.31(m,1 H), 2.14(s,3 H), 2.07(s,6 H), 1.4-1.7(m,4 H),0.96(t,6 H) ppm.

EXAMPLE 1382-[3-Hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-ol

A mixture of4-(s)-(1-hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester and 1M lithium aluminum hydride and aluminum chloridein THF in dry THF was heated at reflux. The mixture was cooled andquenched with water, 2N NaOH, then of water and stirred at roomtemperature for 10 min. White solid formed and was filtered throughcelite, washed with THF. The filtrate was concentrate to dryness to givethe title compound as white solid after column chromatography,

mp. 135-137° C.; Anal. For C₂₀H₂₈N₂O₃ calc. C, 69.74; H, 8.19; N, 8.13;found C, 69.42; H, 8.34; N, 7.95

The following compounds were prepared by the method analogous to that inthe preceding paragraph, starting with the corresponding ester withlithium aluminum hydride and aluminum chloride.

3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-pentan-2-ol

mp. 180-182° C. 1H NMR(CDCl₃) 7.0(s,2 H), 6.18&6.15(two sets of s,1 H),5.1and 5.22(m,1 H), 4.92(m,2 H), 3.80-4.0(m,1 H), 3.20-3.5(m,1 H),2.11(s,3 H), 2.04(s,6 H), 1.4-1.8(m,2 H), 1.23(m,3 H), 0.98(m,3 H) ppm.

2-[2-(2,6-Dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol

1H (CDCl₃) d 7.05(m,3 H), 6.20(s,1 H), 4.8-5.0(m,2 H), 3.74(m,1 H),3.66(m,1 H), 3.50(m,1 H), 2.0-2.29m,9 H), 1.55-1.75(m,2 H), 0.99(t,3 H)ppm.

3-[3-Hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-pentan-2-ol

1H NMR(CDCl₃) d 6.86(s,2 H), 6.17(s, 1 H), 4.0(d,1 H), 3.9(m,1 H),3.3(m,1 H), 2.29(s,3 H), 2.14(s,3 H), 2.13(s,3 H), 2.07(s,6 H), 1.8(d,1H), 1.4-1.8(m,2 H), 1.25(d,3 H), 0.99(t,3 H) ppm.

2-[2-(4-Chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol

1H NMR(CDCl₃) 6.8-7.0(m,3 H), 6.2(s,1 H), 5.02(d,1 H), 4.7(ABq,2 H),3.74(m,5 H), 3.350-3.5(m,2 H), 2.9(brs,2 H), 2.18(s,3 H), 1.4-1.7(m,2H), 1.23(m,3 H), 0.95(t,3 H) ppm.

EXAMPLE 1392-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol

A mixture of4-(s)-(1-hydroxymethyl-propylamino)-6-methyl-2-(4-chloro-2,6-dimethyl-phenoxy)-nicotinicacid methyl ester and 1M lithium aluminum hydride in THF was stirred atrt for 2 hr. The mixture was cooled and quenched with water, 2N NaOH,then of water and stirred at room temperature for 10 min. White solidformed and was filtered through celite, washed with THF. The filtratewas concentrate to dryness to give the title compound as white solidafter column chromatography, mp 133-135° C., 1H NMR(CDCl₃) 7.00(s,2 H),6.17(s,1 H), 5.12(d,1 H), 4.90(m,2 H), 3.4-3.8(m,3 H), 2.12(s,3 H),2.04(s,6 H), 1.4-1.6(m,2 H), 0.99(t,3 H) ppm.

The following compounds were prepared by the method analogous to that inthe preceding paragraph, starting with the corresponding methyl esterwith lithium aluminum hydride:

2{Ethyl-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amino}-ethanol

1H NMR(CDCl₃) d 1H NMR(CDCl3) 6.86(s,2 H), 6.53(s,1 H), 4.94(s,2 H),3.67(m,2 H), 3.1-3.3 (m,4 H), 2.28(s,3 H), 2.20(s,3 H), 2.04(s,6 H),1.09(t,3 H) ppm.

4-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-hexan-3-ol

mp. 145-148° C. 1H NMR(CDCl3) d 1 H NMR(CDCl3) 7.05(s,2 H), 6.16(s,1 H),5.3(d,1 H), 4.94(s,2 H), 3.67(m,1 H), 3.40 (m,1 H), 2.151(s,3 H),2.09(s,6 H), 1.4-1.8(m,4 H), 1.23(m,3 H), 1.02(m,6 H) ppm.

2-[2-(4-Chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR (CDCl₃) d 7.8-7.95(m,2 H), 5.02(d,1 H), 4.74(ABq,2 H), 3.74(s,3H), 3.72(m,2 H), 3.45m,1 H), 2.98(brs,1 H), 2.18(s,3 H), 1.4-1.7(m,2 H),0.95(t,3 H) ppm.

4-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-hexan-3-ol

1H NMR (CDCl₃) d 7.05(s,2 H), 6.16(s,1 H), 5.30(d,1 H), 4.94(s,2 H),3.67(m,1 H), 3.4(m,1 H), 2.15(s,3 H), 2.09(s,6 H), 1.5-1.9(m,4 H), 1.01(m,6 H) ppm.

[2-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

1H NMR(CDCl₃) d 6.90(d,1 H), 6.42(s,1 H), 6.40(d,1 H), 5.91(s,1 H),4.42(m,1 H), 4.28(s,2 H), 3.79(s,3 H), 3.76(s,3 H), 3.56(m,2 H),3.40(s,3 H), 2.33(s,3 H), 1.5-1.85(m,2 H), 1.02(t,3 H) ppm.

EXAMPLE 1402-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid

A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester (113 mg) and lithium hydroxide in dioxane/THF/waterwas stirred at room temperature over night. The mixture was quenchedwith ammonium chloride and extracted with chloroform. The organic layerwas dried and concentrated to give 78 mg of the title compound as awhite solid. 1H NMR(CDCl₃) d 10.55(brs,1 H), 9.2(d,1 H), 7.06(s,2 H),6.3(s,1 H), 3.5-3.8(m,3 H), 2.11(s,3 H), 2.09(s,3 H), 2.08(s,3 H),1.78(m,1 H), 1.62(m,1 H), 1.00(t,3 H) ppm.

4-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid

mp. 131-133° C., 1H NMR(CDCl₃) d 11.29(brs,1 H), 9.35(d,1 H), 6.91(s,2H), 6.38(s,1 H), 4.12(m,1 H), 2.88(m,1 H), 2.32(s,3 H), 2.19(s,3 H),2.09(s,6 H), 1.96(m,2 H), 1.17(t,6 H) ppm.

2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6-methyl-nicotinicacid

1H NMR (CDCl₃) d 10.5(brs, 1 H), 8.6(d,1 H), 7.15(d,2 H), 6.25(s,1 H),3.3-3.6(m,3 H), 3.38(s,3 H), 2.11 (s,3 H), 2.09(s,3 H), 2.08(s,3 H),1.5-1.85(m,2 H), 0.91 (t,3 H) ppm.

4-(2-Methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid

1H NMR(CDCl₃) d 9.44(d,1 H), 6.92(s,2 H), 6.30(s,1 H), 3.80(m,1 H),3.58(m,2 H), 3.44(s,6 H), 2.33(s,3 H), 2.16(s,3 H), 2.10(s,6 H) ppm.

EXAMPLE 141

The following compounds were prepared by reacting the corresponding[2-(substituted-phenoxy)-3-chloromethyl-6-methyl-pyridin-4-yl]-(alkyl)-aminewith an appropriate amine.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-isobutoxymethyl-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

1H NMR(CDCl₃) d 6.94(s,2 H), 6.0(s,1 H), 5.13(d,1 H), 4.7(s,2 H),3.2(m,1 H), 3.16(d,2 H), 2.02(s,3 H), 1.96(s,6 H), 1.8(m,1 H),1.3-1.6(m,4 H), 0.82(t,6 H), 0.8(d,6 H) ppm.

[3-Ethoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine

1 H NMR (CDCl₃) d 6.86(s,2 H), 6.03(s,1 H), 5.30(d,1 H), 4.83(s,2 H),3.58(q,2 H), 3.35(m, 1 H), 2.29(s,3 H), 2.15(s,3 H), 2.06(s,6 H),1.5-1.78(m,4 H), 1.23(t,3 H), 0.967(t,6 H)ppm.

2-[3-Butoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butan-1-ol

1 H NMR(CDCl₃) d 6.85(s,2 H), 6.179s,1 H), 5.3(d,1 H), 4.82(Abq,2 H),3.5-3.8(m,2 H), 3.5(t,2 H), 2.3(s,3 H), 2.15(s,3 H, 2.02(s,6H),1.75(brs,1 H), 1.5-1.8(m,4 H), 1.3-1.5(m,2 H), 1.02(t,3 H), 0.9(t,3H) ppm.

EXAMPLE 142

1-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-ethanol

The title compound was prepared by reacting4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehydewith methyllithium lithium in THF at −78° C. The desired product wasisolated after silica gel column chromatography to give 60.1% ofcolorless oil. 1 H NMR(CDCl₃) d 6.87(s,2 H), 6.06(s,1 H), 5.7(q,1 H),3.3(m,1 H), 2.29(s,3 H), 2.12(s,6 H), 2.069s,3 H), 1.4-1.7(m,4 H),1.59(d,3 H), 0.8-1.0(m,6 H) ppm.

EXAMPLE 143 Acetic acid4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethylester

The title compound was obtained by acetylation of[2-(2,4,6-trimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine.

1H NMR(CCl₃) d 6.84(s,2 H), 6.04(s,1 H), 5.35(s,2 H), 5.23(d,1 H),3.32(m,1 H), 2.28(s,3 H), 2.12(s,3 H), 2.08(s,3 H), 2.07(s,6 H),1.4-1.7(m,4 H), 0.93(t,6 H) ppm.

EXAMPLE 1442-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

The title compound was prepared by reacting2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester with an excess of 1M methyl magnesium bromide in THFat room temperature overnight. Standard work-up procedure to give thetitle compound after silica gel chromatography.

1 H NMR(CDCl₃) d 7.4(brs,1 H), 7.01(s,2 H), 6.13(s,1 H), 3.7(m,1 H),3.6(m,1 H), 3.45(m,1 H), 2.04(s,3 H), 2.03(s,3 H), 2.02(s,3 H),1.5-1.7(m,2 H), 0.98(t,3 H) ppm.

EXAMPLE 145[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

To a solution of[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-chloromethyl-6-methyl-pyridin-4-yl]-(1-ethyl-propylyamine(75 mg, 0.196 mmol) in dry THF was added 1.0M BH₃ in THF (0.59 ml, 0.59mmol) and stirred for 2 hr. The mixture was quenched with dilute HCl andstirred for 5 min. The reaction mixture was neutralized with 2N NaOH,water and extracted with ethyl acetate. The organic layer was separated,dried and concentrated to dryness. The residue was purified throughsilica gel column chromatography to give the title compound as acolorless oil.

1H NMR(CDCl₃) d 7.03(s,2 H), 6.08(s,1 H), 3.73(d,1 H), 3.3(m,1 H),2.15(s,3 H), 2.12(s,3 H), 2.08(s,6 H), 1.4-1.6(m,4 H), 0.96(t,6 H) ppm.

EXAMPLE 146[2-(2,6-Dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol(43 mg, 0.106 mmol) in dry THF was added 1.0M lithium aluminium hydridein diethyl ether (0.25 ml) and aluminum chloride (28 mg). The resultingmixture was stirred at room temperature overnight. The mixture wasquenched with water, 2NaOH, then water. Solid formed and filteredthrough celite, washed with THF, then chloroform. The filtrate wasconcentrated to dryness. The residue was diluted with water and ethylacetate. The organic layer was separated, dried and concentrated to givethe crude material. The title compound was isolated after silica gelchromatography. 1H NMR(CDCl₃) d 6.9-7.1(m,3 H), 6.07(s,1 H), 3.35(d,1H), 3.33(m,1 H), 2.14(s,3 H), 2.13(s,3 H), 2.12(s,6 H), 1.5-1.8(m,4 H),0.97(t,6 H) ppm.

EXAMPLE 147[2-(4-Bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

The title compound was prepared by the method analogous to that inExample 145 as a white solid. 1H NMR(CDCl₃) d 7.19(s,2 H), 6.09(s,1 H),3.36(d,1 H), 3.33(m,1 H), 2.15(s,3 H), 2.12(s,3 H), 2.09(s,6 H),1.4-1.8(m,4 H), 0.97(t,6 H) ppm.

EXAMPLE 1484-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde

To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, n,N-dimethylformamide was added and the resulting mixturewas stirred at −78° C. for 20 min, the dry-ice bath was removed. Afterstirring for 5 min, the mixture was quenched with diluted HCl, water andadjusted to pH7.5 and extracted with ethyl acetate. The organic layerwas separated, dried, and concentrated to dryness. The residue waspurified through silica gel chromatography to give the title compound.1H NMR(CDCl₃) d 9.93(s,1 H), 7.60(s,2 H), 6.10(s,1 H), 3.75(d,1 H),3.35(m1H), 2.17(s,6 H), 2.13(s,3 H), 2.12(s,3 H), 1.4-1.8(m,4 H),0.97(t,6 H) ppm.

EXAMPLE 149{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanol

A mixture of4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehydeand sodium borohydride in methanol was stirred at room temperature.After standard work-up procedure and purification, the title compoundwas obtained as a solid. 1H NMR(CDCl₃) d 7.06(s,2 H), 6.08(s,1 H),4.64(s,2 H), 3.74(d,1 H), 3.33(m,1 H), 2.14(s,3 H), 2.13(s,3 H), 2.11(s,6 H) ppm.

EXAMPLE 150(1-Ethyl-propyl)-[2-(4-methoxymethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

To a solution of(4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanolin dry THF was added 60% NaOH in oil and stirred for 5 min. Excess ofMeI was added and stirred at room temperature for 2 hr. After standardworked up procedure and purification, the title compound was obtained asa clear golden oil. 1H NMR(CDCl₃) d 7.02(s,2 H), 6.06(s,1 H), 4.40(s,3H), 3.72(d,lH), 3.39(s,3 H), 3.36(m,1 H), 2.12(s,3 H), 2.11(s,3 H),2.10(s,6 H), 1.4-1.7(m,4 H), 0.95(t,6 H) ppm.

EXAMPLE 151[2-(4-Ethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, ethyl iodide was added and the resulting mixture was stirredat −78° C. for 30 min, the dry-ice bath was removed. After stirring for5 min, the mixture was quenched with brine and extracted with ethylacetate. The organic layer was separated, dried, and concentrated todryness. The residue was purified through silica gel chromatography togive the title compound. 1H NMR(CDCl₃) d 6.89(s,2 H), 6.07(s,1 H),3.72(d,1 H), 3.34(m,1 H), 2.58(q,2 H), 2.16(s,3 H), 2.12(s,3 H),2.09(s,6 H), 1.4-1.7(m,4 H), 1.25(t,3 H), 0.96(t,6 H) ppm.

EXAMPLE 152 2-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-propan-2-ol

To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, acetone was added and the resulting mixture was stirred at−78° C. for 30 min, the dry-ice bath was removed. After stirring for 5min, the mixture was quenched with brine and extracted with ethylacetate. The organic layer was separated, dried, and concentrated todryness. The residue was purified through silica gel chromatography togive the title compound.1H NMR(CDCl₃) d 7.17(s,2 H), 6.08(s,1 H),3.73(d,1 H), 3.33(m,1 H), 2.19(s,3 H), 2.15(s,3 H), 2.12(s,6 H),1.4-1.7(m,4 H), 1.26(s,6 H), 0.96(t,6 H) ppm.

EXAMPLE 1531-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-ethanol

To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, acetaldehyde was added and the resulting mixture was stirredat −78° C. for 30 min, the dry-ice bath was removed. After stirring for5 min, the mixture was quenched with brine and extracted with ethylacetate. The organic layer was separated, dried, and concentrated todryness. The residue was purified through silica gel chromatography togive the title compound. 1H NMR(CDCl₃) d 7.06(s,2 H), 4.84(m,1 H),6.08(s,1 H), 3.73(d,1 H), 3.35(m,1 H), 2.14(s,3 H), 2.12(s,3 H), 2.11(s,6 H), 1.4-1.7(m,4 H), 1.51 (d,3 H), 0.96(t,6 H) ppm.

EXAMPLE 154(1-Ethyl-propyl)-[2-(4-isopropenyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

The title compound was prepared by reacting of2-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-propan-2-olwith Burgess Inner salt (Et₃NS(O)₂NCOOMe in benzene at reflux for 30min. 1H NMR(CDCl₃) d 7.17(s,2 H), 6.08(s,1 H), 5.34(s,1 H), 5.02(s,1 H),3.72(d,1 H), 3.32(m,1 H), 2.12 and 2.15 (two sets of s, 12 H),1.4-1.6(m,4 H), 0.97(t,6 H) ppm.

EXAMPLE 155(1-Ethyl-propyl)-[2-(4-isopropyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

The title compound was prepared by hydrogenation of(1-ethyl-propyl)-[2-(4-isopropenyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amineusing 10% Pd/C as catalyst in ethyl acetate at 55 psi until all startingmaterial were consumed. The title compound was obtained as an oil afterpurification. 1H NMR(CDCl₃) d 6.93(s,2 H), 6.10(s,1 H), 3.73(brs,1 H),3.36(m,1 H), 2.18(s,3 H), 2.14(s,3 H), 2.12(s,6 H), 1.4-1.8(m,4 H),1.27(d,6 H), 0.98(t,6 H) ppm.

EXAMPLE 156[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-allyl)-amine

The title compound was prepared as a clear oil by reduction of4-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid with lithium aluminum hydride andaluminum chloride. 1H NMR(CDCl₃) d 6.87(s,2 H), 6.08(s,1 H), 5.7-5.9(m,1H), 5.1-5.3(m,2 H), 3.75-4.0(m,2 H), 2.30(s,3 H), 2.16(s,3 H), 2.15(s,3H), 2.08(s,6 H), 1.70(m,2 H), 1.03(t,3 H)ppm.

EXAMPLE 157(1-Ethyl-propyl)-[2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, (PhSO2)2NF was added and the resulting mixture was stirredat −78° C. for 30 min, the dry-ice bath was removed. After stirring for5 min, the mixture was quenched with brine and extracted with ethylacetate. The organic layer was separated, dried, and concentrated todryness. The residue was purified through silica gel chromatography togive the title compound. 1H NMR(CDCl₃) d 6.77(s,1 H), 6.73(s,1 H),6.08(s,1 H), 3.3(m,1 H), 2.12(s,3 H), 2.09(s,6 H), 2.08(s,3 H),1.4-1.8(m,4 H), 0.97(t,6 H)ppm.

EXAMPLE 1582-[2-(2,6-Dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-butan-1-ol

The title compound was prepared by the method analogous to that inExample 146.

1H NMR(CDCl₃) d 7.05(m,3 H), 6.24(s,1 H), 3.4-3.8(m,3 H), 2.24(s,3 H),2.16(s,3 H), 2.10(s,6 H), 1.5-1.8(m,2 H), 0.99(t3 H)ppm.

EXAMPLE 1592-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-ol

To a solution of2-(2,4,6-trimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester in dry THF was added 1.0M lithium aluminium hydride indiethyl ether (0.25 ml) and aluminum chloride. The resulting mixture washeated at reflux for 2 hr. The mixture was quenched with of water,2NaOH, then water and stirred. Solid formed and was filtered throughcelite, washed with water and ethyl acetate. The organic layer wasseparated, dried, concentrated, and purification to give the titlecompound as a white solid. Anal. For C₂₀H₂₈N₂O₂.½H₂O calc. C, 70.90; H,8.52; N, 8.01; found C, 71.18; H, 8.66; N, 8.30

The following compounds were prepared by the method analogous to that inthe preceding paragraph, using the corresponding 2-(substitutedphenoxy)-4-(alkyl-amino)-6-methyl-nicotinic acid methyl ester withlithium aluminum hydride and aluminum chloride.

3-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-pentan-2-ol

1H NMR(CDCl₃) d 6.86(s,2 H), 6.17&6.13(two sets of s, 1 H), 5.0-5.2(m,1H), 4.9(s,2 H), 3.9-4.1(m,1 H), 3.5(m,1 H), 3.3(m,1 H), 2.29(s,3 H),2.14(s,3 H), 2.08(s,6 H), 1.4-1.8(m,2 H), 1.27(m,3 H), 0.98(m,3 H) ppm.

3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pentan-2-ol

1H NMR(CDCl₃) d 7.01(s,2 H), 6.14&6.11(two sets of s,1 H), 4.04&3.82(twosets of d,1 H), 3.92(m,1 H), 3.4&3.2(m,1 H), 2.13(s,3 H), 2.11(s,3 H),2.05(s,6 H), 1.4-1.8(m,2 H), 1.25(two sets of d, 3 H), 0.98&0.96(twosets of t,3 H) ppm.

EXAMPLE 160Benzyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine

A mixture of 4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine(250 mg, 0.78 mmol), benzylethylamine (127 mg, 0.937 mmol), Pd(OAc)2(3.6mg, 0.0156 mmol), (S)-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl(BINAP) (9.7 mg, 0.0156 mmol), potassium t-butoxide (105 mg, 0.781 mmol)in 25 ml of toluene was heated at reflux for 2 hr. The mixture wascooled to rt, quenched with water and extracted with ethyl acetate. Theorganic layer was separated, dried (Na₂SO₄), filtered, and concentratedto give a brown oil. The crude material was purified through silica gelcolumn chromatography to give the title compound. 1H NMR(CDCl₃) d7.2-7.4(m,5 H), 6.86(s,2 H), 6.41(s,1 H), 4.23(s,2 H), 3.07(q,2 H),2.31(s,3 H), 2.29(s,3 H), 2.16(s,3 H), 2.06(s,6 H), 1.05(t,3 H) ppm.

The following compounds were prepared by the method analogous to that inthe preceding paragraph, using an appropriate 4-bromo-2-(substitutedphenoxy)-3-methyl-6-alkyl or alkoxy-pyridine with an appropriate amine.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 7.06(s,2 H), 6.13(s,1 H), 4.14(d,1 H), 3.3-3.6(m,3 H),3.42(s,3 H), 2.16(s,3 H), 2.14(s,3 H), 2.09(s,6 H), 1.5-1.8(m,2 H0,1.03(t,3 H) ppm.

2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-3-phenyl-propan-1-ol

1H NMR(CDCl₃) d 8.6(d,1 H), 7.2-7.4(m5 H), 6.84(s,2 H), 6.169s,1 H),4.099d,1 H), 3.82(m,1 H), 3.5-3.7(m,2 H), 2.95(d,2 H), 2.96(s,3 H),2.27(s,3 H), 2.14(s,3 H), 2.05(s,6 H) ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 7.06(s,2 H), 6.13(s,1 H), 4.2(m,1 H), 3.53(m,2 H),3.42(s,3 H), 2.19(s,3 H), 2.14(s,3 H), 2.10(s,6 H), 1.5-1.8(m,2 H),1.03(t,3 H) ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 7.06(s,2 H), 6.14(s,1 H), 4.24(d,1 H), 4.4-4.65(m,5 H),2.19(s,3 H), 2.14(s,3 H), 2.10(s,6 H), 1.8(m,1 H), 1.65(m,1 H), 1.25(t,3H), 1.03(t,3 H) ppm.

[3,6-Dimethyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 6.20(s,2 H), 6.08(s,1 H), 3.80(s,3 H), 3.73(s,6 H),3.8(m,2 H), 3.39(m,1 H), 3.36(s,3 H), 2.23(brs,3 H), 2.10(s,3 H),1.74(m,1 H), 1.59(m,1 H), 0.969t,3 H) ppm.

[2-(4-Bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethy-propyl)-amine

1H NMR(CDCl₃) d 7.18(s,2 H), 6.09(s,1 H), 4.43(d,1 H), 3.89(s,3 H),3.25(m,1 H), 2.10(s,9H), 1.4-1.8(m,4 H), 0.95(t,6 H) ppm.

(1-Ethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

1H NMR(CDCl₃) d6.85(s,2 H), 6.07(s,1 H), 4.44(m,1 H), 3.89(s,3 H),3.23(m,1 H), 2.27(s,3 H), 2.09(s,6 H), 2.08(s,3 H), 1.65(m,2 H),1.45(m,2 H), 0.93(m,6 H) ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[2-(4-Bromo-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

1H NMR(CDCl₃) d 7.03(s,2 H), 6.13(s,1 H), 3.8(m,1 H), 3.74(s,2 H),3.38(m,1 H), 2.15(s,3 H), 2.05(s,6 H), 1.50-1.7(m,4 H), 0.97(t,6 H) ppm.

(1-Ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

1H NMR(CDCl₃) 7.24(d,1 H), 7.1(d,1 H), 6.1(s,1 H), 4.47(d,1 H), 3.9(s,3H), 3.22(m,1 H), 2.12(s,3 H), 2.08(s,3 H), 1.4-1.7(m,4 H), 0.9(t,6 H)ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

1H NMR(CDCl₃) 7.02(s,2 H), 6.07(s,1 H), 4.44(brs,1 H), 3.8-3.95(m,3 H),3.23(m,1 H), 2.09(s,6 H), 2.08(s,3 H), 1.4-1.7(m,4 H), 0.93(t,6 H)ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 7.02(s,2 H), 6.11(s,1 H), 4.71(d,1 H), 3.88(s,3 H),3.45(m,2 H), 3.37(s,3 H), 2.10(s,3 H), 2.09(s,6 H), 1.73(m,1 H),1.59(m,1 H), 0.98(m,3 H) ppm.

[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR (CDCl₃) d 7.1-7.25(m,2 H), 6.13(s,1 H), 4.74(d,1 H), 3.91(s,3 H),3.47(m,1 H), 3.39(m,2 H), 3.37(s,3 H), 2.14(s,3 H), 2.1 0(s,3 H),1.78(m, 1 H), 1.59(m, 1 H), 0.98(t,3 H)ppm.

[2-(4-Chloro-2-methoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR (CDCl₃) d 6.8-7.0(m,3 H), 6.17(s,1 H), 4.76(d,1 H), 3.82(s,3 H),3.75(s,3 H), 3.3-3.5(m,3 H), 3.35(s,3 H), 2.19(s,3 H), 1.73(m,1 H),1.56(m,1 H), 0.96(t,3 H) ppm.

[2-(3-Chloro-2,6-dimethoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 7.12(d,1 H), 6.64(d,1 H), 6.12(s,1 H)<4.73(d,1 H),3.88(s,3 H), 3.78(s,3 H), 3.70(s,3 H), 3.3-3.5(m,3 H), 3.35(s,3 H), 2.11(s,3 H), 1.5-1.8(m,2 H), 0.96(t,3 H) ppm.

(1-Methoxymethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine

1H NMR(CDCl₃) d 6.19(s,2 H), 6.10s,1 H), 4.75(m,1 H), 3.87(s,3 H),3.80(s,3 H), 3.73(s,6 H), 3.3-3.5(m,2 H), 3.35(s,3 H), 2.17(s,3 H),1.78(m,1 H), 1.5(m,1 H), 0.96(t,3 H) ppm.

[3-Methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-yl]-(1-ethoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 6.59(s,2 H), 6.10(s,1 H), 4.70(d,1 H), 3.89s,3 H),3.77(s,3 H), 3.48(m,1 H), 3.39(m,2 H), 3.37(s,3 H), 2.11(s,3 H),2.10(s,6 H), 1.74(m,1 H), 1.57(m,1 H), 0.98(t,3 H) ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-ethoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

1H NMR(CDCl₃) d 7.07(s,2 H), 6.16(s,1 H), 4.82(d,1 H), 4.20(q,2 H),3.54(m,1 H), 3.43(m,2 H), 3.42(s,3 H), 2.15(s,3 H), 2.13(s,6 H),1.5-1.9(m,2 H), 1.439t,3 H), 1.02(t,3 H) ppm.

EXAMPLE 1612-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-(S)-ylamino]-butan-1-ol

To a solution of[1-(tert-butyl-dimethyl-silanyloxymethyl)-propyl]-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-aminein dry THF was added 1 M tetrabutylammonium fluoride in THF at roomtemperature. The mixture was stirred at room temperature for 2 hr,quenched with water, extracted with ethyl acetate. The organic layer wasseparated, dried and concentrated to dryness. The residue was purifiedby Biotage using 15% ethyl acetate in hexane as eluent to give the titlecompound as a white solid. 1H NMR(CDCl₃) d 7.06(s,2 H), 6.18(s,1 H),4.04(d,1 H), 3.74(m,1 H), 3.69(m,1 H), 3.53(m,1 H), 2.18(s,3 H),2.16(s,3 H), 2.10(s,6 H), 1.6-1.8(m,2 H), 1.04(t,3 H) ppm.

The following compounds were prepared by the method analogous to that inthe preceding paragraph, starting with the correspondingtert-butyl-dimethyl-silanyloxymethyl derivative with tetrabutylammoniumfluoride.

2-[3-Methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR (CDCl₃) d 6.85(s,2 H), 6.15(s,1 H), 4.57(d,1 H), 3.91(s,3 H),3.72(m,1 H), 3.61(m,1 H), 3.41(m,1 H), 2.27(s,3 H), 2.10(s,3 H),2.07(s,6 H), 1.5-1.8(m,3 H), 0.98(t,3 H) ppm.

2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.02(s,2 H), 6.16(s,1 H), 4.60(d,1 H), 3.91(s,3 H),3.71(m,1 H), 3.61(m,1 H), 3.40(m,1 H), 2.10(s,3 H), 2.08(s,6 H),1.8(brs,1 H), 1.71(m,1 H), 1.68(m,1 H), 0.99(t,3 H) ppm.

4-[4-(1-Hydroxymethyl-propylamino)-3-methoxy-6-methyl-pyridin-2-yloxy]-3,5-dimethyl-benzonitrile

1H NMR(CDCl₃) d 7.35(s,2 H), 6.19(s,1 H), 4.7(brs,1 H), 3.88(s,3 H),3.731(m,1 H), 3.64(m,1 H), 3.43(m,1 H), 2.14(m,9 H), 1.8(brs,1 H),1.71(m,1 H), 1.58(m,1 H), 0.99(t,3 H) ppm.

EXAMPLE 1623-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pentan-2-ol

The title compound was prepared by Dess Martin oxidation of2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-(S)-ylamino]-butan-1-olmethylene chloride at room temperature, followed by Gringard reactionusing methyl magnesium bromide in THF.1H NMR(CDCl₃) d 7.07(s,2 H),6.18(s,1 H), 4.3(brs,1 H), 4.0(m,1 H), 3.32(m,1 H), 2.22(s,3 H),2.17(s,3 H), 2.11 (s,6 H), 1.6-1.8(m,2 H), 1.30(d,3 H), 1.01 (t,3 H)ppm.

EXAMPLE 1632-[2-Methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butan-1-ol

The title compound was prepared as an oil by heating2-(2,4,6-trimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid in 160° C. until all starting material were consumed. Anal. ForC₁₉OH₂₆N₂O₂ H₂O calc. C, 68.65; H. 8.49; N, 8.42; found C, 69.04; H,8.14; N, 8.91

EXAMPLE 164(1-Ethyl-prop-2-ynyl)-[2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

The title compound was prepared by the method analogous to that inExample 163.

1H NMR(CDCl₃) d 6.89(s,2 H), 6.12(d,1 H), 5.41(d,1 H), 3.9-4.2(m,2 H),2.37s,3 H), 2.30(s,3 H), 2.27(m,1 H), 1.76(m,2 H), 1.05(t,3 H) ppm.

EXAMPLE 1652-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-ol

To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethy-propyl)-aminein methylene chloride was added BBr₃ at 0° C. and stirred for hr. Themixture was quenched with water and extracted with chloroform. Theorganic layer was separated, dried, and concentrated to give the titlecompound. 1H NMR(CDCl₃) d 7.20(s,2 H), 6.12(s,1 H), 4.77(d,1 H),3.27(m,1 H), 2.13(s,3 H), 2.1 0(s,6 H), 1.4-1.8(m, 4 H), 0.97(t,6 H)ppm.

The following compounds were prepared by the method analogous to that inthe preceding paragraph, starting with an appropriate [2-(substitutedphenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(alkyl)-amine with BBr₃ orBCl₃.

4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol

1H NMR(CDCl₃) d6.85(s,2 H), 6.10(s,1 H), 5.12(brs,1 H), 4.21(m,1 H),3.27(m,1 H), 2.28(s,3 H), 2.09(s,9 H), 1.5-1.8(m,4 H), 0.96(m,6 H) ppm.

4-(S)-(1-Hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol

1H NMR (CDCl₃) d 6.85(s,2 H), 6.17(s,1 H), 5.13(brs,1 H), 4.28(d,1 H),3.73(m,1 H), 3.60(m,1 H), 3.50(m,1 H), 2.27(s,3 H), 2.12(s,3 H),?.07(s,6 H), 1.75(brs,1 H), 1.5-1.7(m,2 H), 0.99(t,3 H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-pyridin-3-ol

1H NMR(CDCl₃) d 7.032(s,2 H), 6.10(s,1 H), 5.2(brs,1 H), 4.35(brs,1 H),3.71(m,1 H), 3.61 (m,1 H), 3.40(m,1 H), 2.07(s,9 H), 1.8(brs, 1 H), 1.71(m,1 H), 1.60(m,1 H), 0.99(m,3 H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-ol

1H NMR(CDCl₃) d 7.02(s,2 H), 6.10(s,1 H), 5.02(brs,1 H), 4.22(brs,1 H),3.25(brs,1 H), 2.08(brs,9 H), 1.62(m,2 H), 1.52(m,2 H), 0.95(brs,6 H)ppm.

EXAMPLE 166 Chloro-acetic acid4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylester

The title compound was prepared by reacting4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-olwith chloroacetyl chloride /triethylamine in THF at 0° C. to rt. 1HNMR(CDCl₃) d 6.84(s,2 H), 6.15(s,1 H), 4.3(s,2 H), 4.0(d,1 H), 3.3(m,1H), 2.28(s,3 H), 2.17(s,3 H), 2.08(s,6 H), 1/6-1.7(m,4 H), 0.9(t,6 H)ppm.

EXAMPLE 1672-(4-Chloro-2,6-dimethyl-phenoxy)-4-[(1-ethyl-propyl)-methyl-amino]-6-methyl-pyridin-3-ol

1H NMR(CDCl₃) d 7.03(s,2 H), 6.25(s,1 H), 5.4(brs,1 H), 3.93(m,1 H),2.70(s,3 H), 2.12(s,3 H), 2.08(s,6 H),1.55(m,4 H), 0.89(t,6 H) ppm.

EXAMPLE 168[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetonitrile

1H NMR(CDCl₃) d 6.87(s,2 H), 6.13(s,1 H), 3.83(d,1 H), 3.79(S,2 H),3.38(m,1 H), 2.30(s,3 H), 2.27(s,3 H), 2.21 (s,6 H), 1.4-1.8(m,4 H),1.00(t,6 H) ppm.

EXAMPLE 1694-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehyde

1H NMR(CDCl₃) d 10.52(s,1 H), 9.26(d,1 H), 6.89(s,2 H), 6.11(s,1 H),3.42(m,1 H), 2.31 (s,3 H0, 2.15(s,3 H), 2.11 (s,6 H), 1.45-1.75(m,4 H),0.97(t,6 H) ppm.

EXAMPLE 170(1-Ethyl-propyl)-[3-[(1-ethyl-propylimino)-methyl]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

1H NMR(CDCl₃) d 10.33(d,1 H), 8.94(s,1 H), 6.89(s,2 H), 6.10(s,1 H),3.41(m,1 H), 2.86(m,1 H), 2.99(s,3 H), 2.14(s,3 H), 2.10(s,6 H),1.4-1.89m,8 H), 0.94(t,6 H), 0.87(t,6 H) ppm.

EXAMPLE 1712-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid dimethyl ester

To a solution of dimethylmalonate (60 mg, 0.44 mmol) and 60% NaH in oil(20 mg, 0.44 mmol) in dry THF was added the title compound of Example 85(50 mg, 0.146 mmol) at room temperature for 1 hr. The mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas separated, dried and concentrated to dryness. The residue waspurified through silica gel column chromatography to give the titlecompound as a clear oil. 1H NMR (CDCl₃) d 6.88(s,2 H), 6.03(s,1 H),4.85(m,1 H), 4.03(t,1 H), 3.73(s,6 H), 3.26(m,1 H), 3.18(d,2 H),2.30(s,3 H), 2.13s,3 H), 2.07(s,6 H), 1.5-1.8(m,4 H), 0.97(t,6 H)ppm.

EXAMPLE 1722-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid diisopropyl ester

The title was prepared by the method analogous to that in Example 171.1H NMR (CDCl₃) d 6.87(s,2 H), 6.03(s,1 H), 5.10(m,2 H), 4.90(d,1 H),3.94(t,1 H), 3.31(m,1 H), 3.16(d,2 H), 2.30(s,3 H), 2.13s,3 H0, 2.08(s,6H), 1.5-1.8(m,4 H), 1.1-1.3(two sets of d, 6 H), 0.97(t,6 H)ppm.

EXAMPLE 1734-(1-Ethyl-propoxy)-6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridine

To a mixture of 2-chloro-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridine(500 mg, 1.93 mmol) and 2,4,6-trimethylphenol (289 mg, 2.13 mmol) in dryTHF was added potassium t-butoxide. The resulting mixture was stirred atrt. overnight. The mixture was quenched with water, brine and extracted3 times with ethyl acetate. The organic layer was separated, dried(MgSO₄) and concentrated to dryness. After silica gel columnchromatography purification, the title compound was obtained as a lightyellow crystal, mp 106-109° C. Anal. For C₂₀H₂₆N₂O₄ calc. C, 67.02; H,7.31; N, 7.82; found, C, 67.34; H, 7.40; N, 7.42.

EXAMPLE 1744-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine

A mixture of4-(1-ethyl-propoxy)-6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridine(150 mg, 0.418 mmol) and 10% Pd/C (23 mg) in ethanol was hydrogenated at50 psi for 15 hours. An additional 10 Pd/C was added and the resultingmixture was hydrogenated for an additional 24 hr. The mixture wasfiltered through celite and the filtrate was concentrated to dryness togive 200 mg of the crude material. After column chromatography, thetitle compound was prepared as a the corresponding HCl salt as a whitesolid, mp 96-98° C.

EXAMPLE 175[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-dimethyl-amine

To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylaminein dry THF was added lithium bis(trimethylsilyl)amide at −78° C. Afterstirring at −78° C. for 10 minutes, an excess of methyl iodide wasadded. The title compound was isolated after quenching with water andextracting with ethyl acetate. The crude material was purified by silicagel column chromatography to give the title compound as a tan foam.

EXAMPLE 176N-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-succinamicacid

A mixture of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine(100 mg, 0.304 mmol), succinic anhydride 31 mg,0.304 mmol) andtriethylamine in methylene chloride was stirred at rt. overnight. Themixture was quenched with water, and extracted with methylene chloride.The organic layer was separated, dried and concentrated to give a solid.The title compound was isolated as a white crystal after silica gelcolumn chromatography.

1H NMR(CDCl₃) d 6.90(brs,1 H), 6.84(s,2 H), 6.37(s,1 H), 4.2(m,1 H),2.6-2.8(m,4 H), 2.28(s,3 H), 2.22(s,3 H), 2.03(s,6 H), 1.69(m,4 H),0.94(t,6 H) ppm.

EXAMPLE 1774-(1-Ethyl-propoxy)-3,6-dimethyl-2-[3-(2,4,6-trimethyl-pyridinoxy)]-pyridine

To a solution of 3-pentanol (0.11 ml) in dry THF was added sodiumhydride (60% in oil, 20 mg). After stirring for 5 min, a solution of4-chloro-2,5-dimethyl-6-[3-( 2,4,6-trimethyl-pyridinoxy)]-pyridine (92mg, 0.332 mmol) in THF was added. DMSO was added and the resultingmixture was heated at 130° C. oil bath overnight. The mixture wasquenched with water, brine and extracted 3 times with ethyl acetate. Theorganic layer was separated, dried (MgSO₄) and concentrated to dryness.After silica gel column chromatography purification, the title compoundwas obtained as a clear oil. 1H NMR (CDCl₃) d 6.88 (s,1 H), 6.37(s,1 H),4.21(m,1 H), 2.5(s,3 H), 2.29(s,3 H), 2.19(s,3 H), 2.18(s,3 H), 2.07(s,3H), 1.70(m,4 H), 0.98(t,6 H) ppm. The oil was prepared as thecorresponding HCl salt to give a white solid (63 mg).

The title compounds of the following Examples 178 and 179 were preparedby the methods analogous to that in Example 177, starting with anappropriate 6-alkyl-4-chloro-orbromo-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine with 3-pentanol/NaH:

EXAMPLE 1786-Ethyl-4-(1-ethyl-propoxy)-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

1H NMR(CDCl₃) d 6.87(s,2 H), 6.28(s,1 H), 4.20(m,1 H), 2.46(q,2 H),2.30(s,3 H), 2.20(s,3 H), 2.07(s,6 H), 1.72(m,4 H), 1.05(t,3 H),0.99(t,6 H) ppm.

EXAMPLE 1794-(1-Ethyl-propoxy)-2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

colorless oil. Anal. For C₂₀H₂₆FNO₂ calc. C, 72.48; H, 7.91; N, 4.23;found C, 72.39; H, 7.77; N, 4.10.

EXAMPLE 180[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine

To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid (240 mg, 0.673 mmol) in dry THF was added lithium aluminum hydrideand aluminum chloride. The resulting mixture was heated at reflux for 3hours. The mixture was quenched with 0.1 ml water and 0.1 ml 2N NaOH ,then quenched with water and ethyl acetate. The organic layer wasseparated, dried and concentrated to give 250 mg of brown oil. Aftersilica gel column chromatography, 170 mg(78%) of the title compound wasobtained which was prepared as a HCl salt as a white solid, mp. 132-133°C. 1H NMR(CDCl₃) d 6.87(s,2 H), 6.09(s,1 H), 5.399brs,1 H), 4.13(m,1 H),2.27(s,3 H), 2.22(s,3 H), 2.15(s,6 H), 1.98(s,3 H), 1.67(m,4 H),0.94(t,6 H) ppm.

EXAMPLE 181[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol

To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid (100 mg, 0.281 mmol) in dry THF was added BH₃.DMS. The resultingmixture was heated at reflux overnight. The mixture was quenched withdilute HCl and stirred for 30 minutes, adjusted pH to 7.5-8.5, thenextracted with ethyl acetate. The organic layer was separated, dried andconcentrated to give 100 mg of brown oil. After silica gel columnchromatography, 91 mg(95%) of the title compound was obtained as a whitefoam. Anal. For C₂₁H₃₀N₂O₂.½H₂O cal. C, 71.76; H, 8.89; N, 7.97; found:C, 71.97; H, 8.90; N, 7.69.

EXAMPLE 182[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-oxo-acetonitrile

The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with diethylaluminum cyanide. After standard workup procedureand silica gel column chromatography, compound was obtained as a yellowcrystal, mp. 108-110° C.

1H NMR(CDCl₃) d 8.57(s,1 H), 6.97(s,2 H), 6.37(s,1 H), 4.46(m,1 H),2.35(s,3 H), 2.34(s,3 H), 2.09(s,6 H), 1.6-1.8(m,4 H), 0.99(t,6 H) ppm.

EXAMPLE 183[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-imidazol-1-yl-methanone

To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid (250 mg, 0.701 mmol) in 2 ml of DMF was added carbonyldiimidazole(190 mg, 1.19 mmol) and the resulting mixture was stirred at roomtemperature overnight. After standard workup procedure and silica gelcolumn chromatography, 260 mg(91.2%) of the title compound was obtainedas a golden-crystal, mp. 120-122° C., Anal. For C₂₄H₃₀N₄O₂.¼H₂O calc: C,70.13; H, 7.48; N, 13.63; Found: C, 70.06; H, 7.69; N, 13.37.

EXAMPLE 1842-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-propan-2-ol

The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-imidazol-1-yl-methanonewith an excess MeMgBr in THF at rt. After standard workup procedure andsilica gel column chromatography, the title compound was obtained as atan solid, mp. 81-83° C.; Anal. For C₂₂H₃₀N₂O₂. 1.5 H₂O calc.: C,69.49;H, 9.38; N, 7.04; found: C, 69.49; H, 9.27; N, 6.86

EXAMPLE 1852-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonicacid dimethyl ester

The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with methyl malonate/NaH in DMSO. After standard workupprocedure and silica gel column chromatography, the title compound wasobtained as a solid, mp. 96-98° C.; Anal. For C₂₆H₃₆N₂O₅. ⅓H₂O calc.:C,67.51; H, 7.99; N, 6.04; found: C, 67.48; H, 7.99; N, 6.02.

EXAMPLE 1863-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-propionicacid

Hydrolysis of2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonicacid dimethyl ester with phosphoic/water at reflux to give the titlecompound as a white foam. Anal. For C₂₃H₃₂N₂O₃. ¾H₂O calc.: C,69.40; H,8.48; N, 7.04; found: C, 69.17; H, 8.62; N, 6.90.

EXAMPLE 187[3-Aminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine

The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanol with thionyl chloride in benzene, concentratedto dryness, followed by reacting with NH₃(g) at room temperature. Afterstandard workup procedure and silica gel column chromatography, thetitle compound was obtained as a golden oil (80%), Anal. For C₂₁H₃₁N₃O.calc.: C,73.86; H, 9.15; N, 12.3; found: C, 73.50; H, 9.25; N, 11.39.

EXAMPLE 1882-Chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-acetamide

The title compound was prepared by acylation of3-aminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine with chloroacetyl chloride. After standardworkup procedure and silica gel column chromatography, the titlecompound was obtained as an off-white crystal, mp. 142-144° C.; Anal.For C₂₃H₃₂ClN₃O₂. calc.: C,66.09; H, 7.72; N, 10.05; found: C, 65.81; H,7.64; N, 9.86.

EXAMPLE 189[3-Dimethylaminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-aminehydrochloride salt

The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with dimethylamine at room temperature. After standard work-upprocedure and silica gel column chromatography, the title compound wasobtained as an oil. The corresponding HCl salt was prepared as a whitesolid, mp. 85-88° C.; Anal. For C₂₃H₃₅N₃O.2HCl. 1.5 H₂O calc.: C,58.83;H, 8.588; N, 8.94; found: C, 58.32; H, 8.5327; N, 8.64.

EXAMPLE 190 Dithiocarbonic acid O-ethyl esterS-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]ester

The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with NaSCSOEt at room temperature. After standard work-upprocedure and silica gel column chromatography, the title compound wasobtained as a white solid, mp. 55-57° C.; Anal. For C₂₄H₃₄N₂O₂S₂. calc.:C,64.54; H, 7.67; N, 6.27; found: C, 64.67; H, 7.78; N, 6.26.

EXAMPLE 1914-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide

The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid with thionyl chloride in benzene, concentrated to dryness, followedby reacting with NH₃(g) at room temperature. After standard work-upprocedure and silica gel column chromatography, the title compound wasobtained an oil. The corresponding HCl salt was prepared as an off-whitesolid, mp 185-187° C.; Anal. For C₂₁H₂₉N₃O₂. calc.: C,70.96; H, 8.22; N,11.82; found: C, 71.30; H, 8.33; N, 11.78.

EXAMPLE 1924-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinonitrile

The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamidewith triphosgen/triethylamine in THF. mp 105-107° C., 1H NMR(CDCl₃) d6.90(s,2 H), 6.26(brs,1 H), 6.05(s,1 H), 4.24(m,1 H), 2.28(s,3 H),2.25(s,3 H), 2.17(s,6 H), 1.72(m,4 H), 0.97(t,6 H) ppm.

EXAMPLE 1934-(1-Ethyl-propoxy)-6,N,N-trimethyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide

The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid with thionyl chloride in benzene, concentrated to dryness, followedby reacting with dimethylamine at room temperature. After standardwork-up procedure and silica gel column chromatography, the titlecompound was obtained an oil. The corresponding HCl salt was prepared asa white solid, mp. 197-200° C.; Anal. For C₂₃H₃₃N₃O₂.H₂O. calc.:C,63.07; H, 8.28; N, 9.59; found: C, 63.24; H, 8.07; N, 9.61.

EXAMPLE 194[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethy!-phenylamino)-pyridin-3-yl]-acetonitrile

The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with potassium cyanide in DMSO at room temperature. Afterstandard work-up procedure and silica gel column chromatography, thetitle compound was obtained as a pale orange solid, mp. 112-115° C., 1HNMR(CDCl₃) d 6.9(s,2 H), 6.14(s,1 H), 5.6(brs,1 H), 4.22(m,1 H),3.49(s,2 H), 2.28(s,3 H), 2.22(s,3 H), 2.16(s,6 H), 1.71(m,4 H),0.95(t,6 H) ppm.

EXAMPLE 195[2-(4-Bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(4-bromo-2,6-dimethyl-phenylamino)-nicotinicacid (130 mg, 0.309 mmol) in dry THF was added BH₃.DMS. The resultingmixture was heated at reflux overnight. The mixture was quenched withdilute HCl and stirred for 30 min, adjusted pH to 7.5-8.5, thenextracted with ethyl acetate. The organic layer was separated, dried andconcentrated to give 100 mg of brown oil. After silica gel columnchromatography, 110 mg(87.3%) of the title compound was obtained as awhite semi-solid. 1H NMR(CDCl₃) d 7.25(s,2 H), 6.85(brs,1 H), 4.8(brs,2H), 4.18(m,1 H), 2.2(s,3 H), 2.07(s,6 H), 1.7(m,4 H), 0.95(t,6 H) ppm.

EXAMPLE 196[2-(4-chloro-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(4-chloro-2,6-dimethyl-phenylamino)-nicotinicacid in dry THF was added BH₃.DMS. The resulting mixture was heated atreflux overnight. The mixture was quenched with dilute HCl and stirredfor 30 minutes, adjusted pH to 7.5-8.5, then extracted with ethylacetate. The organic layer was separated, dried and concentrated to givea brown oil. After silica gel column chromatography, the title compoundwas obtained as a green oil. 1H NMR(CDCl₃) d 7.02(s,2 H), 6.83(brs,1 H),4.78(s,2 H), 4.14(m, 1 H), 2.2(s,3 H), 2.13(s,6 H), 1.66(m,4 H),0.93(9t,6 H) ppm.

EXAMPLE 197[2-(2,4-Dichloro-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4-dichloro-phenylamino)-nicotinic acidin dry THF was added BH₃.DMS. The resulting mixture was heated at refluxovernight. The mixture was quenched with dilute HCl and stirred for 30min, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to give a goldenoil. After silica gel column chromatography, the title compound wasobtained as a golden oil. 1H NMR(CDCl₃) d 8.44(d,1 H), 8.18(s,1 H),7.32(d,1 H), 7.179d,1 H), 6.28(s,1 H), 4.82(s,2 H), 4.21 (m,1 H),2.42(s,3 H), 1.6-1.8(m,4 H), 0.94(t,6 H) ppm.

EXAMPLE 198[2-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

The title compound was prepared by a method analogous to that describedfor Example 197, starting with the corresponding nicotinic acid withBH₃.DMS. 1H NMR(CDCl₃) d 6.91(d,1 H), 6.50(m,2 H),5.91(s,1 H), 4.42(m,1H), 4.281(s,2 H), 3.79(s,3 H), 3.76(s,3 H), 3.56(m,2 H), 3.40(s,3 H),2.33(s,3 H), 1.6-1.8(m,2 H), 1.02(t,3 H) ppm.

EXAMPLE 199[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone

The title compound was prepared by a method analogous to that describedfor Example 183, starting with the corresponding nicotinic acid withcarbonyldiimidazole. 1HNMR(CDCl₃) d 8.1(s,1 H), 7.52(s,1 H), 7.05(s,1H), 6.78(s,2 H), 6.17(s,1 H), 5.97(d,1 H), 3.3(m, 1 H), 2.23(s,3 H),2.18(s,3 H), 2.00(s,6 H), 1.4-1.7(m,4 H), 0.93(t,6 H) ppm.

EXAMPLE 2001-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-ethanone

The title compound was prepared by reacting[4-(1-Ethyl-propylamino)6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone withmethylmagnesium bromide/ethyl ether in methylene chloride. 1H NMR(CDCl₃)d 9.7(d,1 H), 6.88(s,2 H), 6.10(s,1 H), 3.32(m,1 H), 2.73(s,3 H),2.31(s,3 H), 2.10(s,3 H), 2.09(s,6 H), 1.5-1.7(m,4 H), 0.95(t,6 H)ppm.

EXAMPLE 201(1-Ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

1H NMR(CDCl₃) d 6.84(s,2 H), 6.04(s,1 H), 3.81(d,1 H), 3.31(m,1 H),2.56(t,2 H), 2.27(s,3 H), 2.12(s,3 H), 2.04(s,6 H), 1.4-1.7(6 H),1.02(t,3 H), 0.93(t,6 H) ppm.

EXAMPLE 2022-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-2-methyl-malonicacid dimethyl ester

The title compound was prepared by a method analogous to that describedfor Example 185. 1H NMR(CDCl₃) 6.87(s,2 H), 6.01(s,1 H), 5.05(m,1 H),3.70(s,6 H), 3.4(s,2 H), 3.3(m,1 H), 2.27(s,3 H), 2.12(s,3 H), 2.07(s,6H), 1.4-1.7(m,4 H), 1.48(s,3 H), 0.949t,6 H) ppm.

EXAMPLE 203 [4-(1-Ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenylyamine

The title compound was prepared by decarboxylation of the correspondingnicotinic acid af 160° C. oil bath. mp. 98-100° C.; Anal. For C₂₀H₂₈N₂Ocalc. C, 76.88; H, 9.03; N, 8.97; found: C, 76.97; H, 9.21; N, 8.99.

The following title compounds of Examples 204 and 205 were prepared byreacting of3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-4-carbaldehydewith alkyl-magnesium bromide in THF:

EXAMPLE 2042-Ethyl-1-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butan-1-ol

1H NMR(CDCl₃) 6.87(s,2 H), 6.72(s,1 H), 4.90(t,1 H), 4.00(s,3 H),2.29(s,3 H), 2.19(s,3 H), 2.06(s,6 H), 1.2-1.6(m,5 H), 0.92(t,3 H),0.88(t,3 H) ppm.

EXAMPLE 2051-[3-Methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2-methyl-butan-1-ol

1H NMR(CDCl₃) 6.88(s,2 H), 6.74(s,1 H), 5.00(m,1 H), 4.00(s,3 H),2.29(s,3 H), 2.19(s,3 H), 2.06(s,6 H), 1.4-1.9(m,3 H), 0.992(t,3 H),0.989(d,3 H) ppm.

EXAMPLE 2061-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol

To a −78° C. solution of4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine in dry THF wasadded nBuLi and stirred at that temperature for 20 minutes. Excesspropionaldehyde was added and stirred for 2 hours at −78° C. The mixturewas quenched with water, extracted with ethyl acetate. The organic layerwas washed with brine, dried and concentrated. After columnchromatography, an off-white solid was obtained, mp. 119-120° C.1HNMR(CDCl₃) d 6.86(s,3 H), 4.90(m,1 H), 2.281(s,3 H), 2.28(s,3 H),2.21(s,3 H), 2.02(s,6 H), 1.65-1.8(m,2 H), 1.00(t,3 H) ppm.

EXAMPLE 2074-(1-Methoxy-propyl-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

The title compound was prepared by reaction of1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-olwith sodium hydride, followed by quenching with methyl iodide. 1HNMR(CDCl₃) d 6.87(s,2 H), 6.74(s,1 H), 4.33(m,1 H), 3.25(s,3 H),2.28(s,3 H), 2.27(s,3 H), 2.21 (s,3 H), 2.03(s,6 H), 1.6-1 .8(m,2 H),0.94(t,3 H) ppm.

EXAMPLE 2084-(1-Ethoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

The title compound was prepared by reaction of1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-olwith sodium hydride, followed by quenching with ethyl iodide.

1H NMR(CDCl₃) d 6.86(s,2 H), 6.77(s,1 H), 4.41(m,1 H), 3.22-3.45(m,2 H),2.28(s,3 H), 2.27(s,3 H), 2.21 (s,3 H), 2.03(s,6 H), 1.6-1.8(m,2 H),1.20(t,3 H), 0.95(t,3 H) ppm.

EXAMPLE 2094-(1-Allyloxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

The title compound was prepared by reaction of1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-olwith sodium hydride, followed by quenching with allyl bromide.

1H NMR(CDCl₃) d 6.87(s,2 H), 6.78(s,1 H), 5.93(m,1 H), 5.1-5.3(m,2 H),4.48(m,1 H), 3.95(m,1 H), 3.76(m,1 H), 2.29(s,3 H), 2.26(s,3 H),2.21(s,3 H), 2.03(s,6 H), 1.6-1.8(m,2 H), 0.96(t,3 H) ppm.

EXAMPLE 2104-(1-Butoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

The title compound was prepared by reacting of1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-olwith sodium hydride, followed by quenching with butyl iodide.

1H NMR(CDCl₃) d 6.86(s,2 H), 6.76(s,1 H), 4.37(m,1 H), 3.35(m,1 H),3.25(m,1 H), 2.28(s,3 H), 2.26(s,3 H), 2.20(s,3 H), 2.03(s,6 H),1.6-1.8(m,2 H), 1.5-1.65(m,2 H), 1.3-1.5(m,2 H), 0.96(t,3 H), 0.89(t,3H) ppm.

The title compounds of the following Examples 211 through 215 wereprepared by a method analogous to that described in 206 starting with anappropriate 4-bromo-2-(substituted-phenoxy)-pyridine derivative withnBuLi, followed by quenching with an appropriate aldehyde.

EXAMPLE 2111-[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-ol

one racemate 1H NMR(CDCl₃) d 7.28(d,1 H), 7.14(d,1 H), 6.80(s,1 H),4.92(d,1 H), 4.00(s,3 H), 2.21(s,3 H), 2.13(s,3 H), 1.3-1.65(m,5 H),0.93(t,3 H), 0.87(t,3 H) ppm.

The other racemate 1H NMR (CDCl₃) d 7.18(s,1 H), 7.08(d,1 H), 6.74(d,1H), 5.17(m,1 H), 3.93(s,3 H), 2.75(m,1 H), 2.1-2.25(m,1 H), 2.16(s,3 H),2.13(s,3 H), 1.6-1.8(m,2 H), 1.0-1.3(m,2 H), 0.93(t,3 H), 0.72(t,3 H)ppm.

EXAMPLE 2121-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2,2,2-trifluoro-ethanol

mp. 134-139° C., Anal. For C₁₈H₂₀F₃NO₂ calc.: C, 63.71; H, 5.94; N,4.13; found: C, 63.59; H, 6.00; N, 4.02.

EXAMPLE 2131-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trifluoro-ethanol

1H NMR(CDCl₃) d 6.979s,2 H), 6.19(s,1 H), 2.14(s,6 H), 2.06(s,6 H) ppm.

EXAMPLE 214[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyridin-2-yl-methanol

1H NMR(CDCl₃) d 8.61 (d, 1 H), 7.71 (m,1 H), 7.30(m, 1 H), 7.10(m, 1 H),7.03(s,2 H),6.70(s,1 H), 6.03(s,1 H), 2.37(s,3 H), 2.16(s,3 H), 2.03(s,6H), ppm.

EXAMPLE 2151-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-ol

1H NMR(CDCl₃) d 7.05(s,2 H), 6.759s,1 H), 4.90(t,1 H), 3.98(s,3 H),2.19(s,3 H), 2.06(s,6 H), 2.13(d,1 H), 1.25-1.65(m,5 H), 0.92(t,3 H),0.87(t,3 H) ppm.

The title compounds of the following Examples 216 through 219 wereprepared by oxidation of the corresponding alcohol with Dess Martinreagent in DMSO/methylene chloride or pyridinium chlorochromate inmethylene chloride.

EXAMPLE 2161-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-one

mp. 82-85.5° C., Anal. For C₁₉H₂₅NO₂ calc.: C, 76.74; H, 7.80; N, 4.71;Found: C, 76.61; H, 7.94; N, 4.66.

EXAMPLE 2171-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trifluoro-ethanone

1H NMR(CDCl3) d 7.06(s,2 H), 6.99(s,1 H), 2.42(s,3 H), 2.30(s,3 H),2.03(s,6 H) ppm.

EXAMPLE 218[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyridin-2-yl-methanone

1H NMR(CDCl₃) d 8.72(d,1 H), 8.17(d,1 H), 7.95(m,1 H), 7.52(m,1 H),7.05(s,2 H),6.75(s,1 H), 2.25(s,3 H), 2.22(s,3 H), 2.07(s,6 H) ppm.

EXAMPLE 2191-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one

1H NMR(CDCl₃) d 7.05(s,2 H), 6.67(s,1 H), 3.98(s,3 H), 3.09(m,1 H),2.61(s,3 H), 2.06(s,6 H), 1.76(m,2 H), 1.51 (m,2 H), 0.92(t,6 H) ppm.

EXAMPLE 2204-(1-Ethoxy-2,2,2-trifluoro-ethyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

The title compound was prepared by reacting the corresponding alcoholwith NaH, followed by quenching with ethyl iodide.

1H NMR(CDCl₃) d 6.92(s,1 H), 6.87(s,2 H), 4.92(m,1 H), 3.60(m2 H),2.349s,3 H), 2.29(s,3 H), 2.26(s,3 H), 2.03(s,6 H), 1.26(t,3 H) ppm.

The title compounds of the following Examples 221 through 222 wereprepared by reacting of the corresponding ketone with alkyl lithium oralkyl magnesium.

EXAMPLE 2212-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butan-2-ol

1H NMR(CDCl₃) d 6.86(m,3 H), 2.48(s,3 H), 2.28(s,3 H), 2.21(s,3 H),2.02(s,6 H), 1.8-2.1(m,2 H), 1.61(s,3 H), 0.84(t,3 H) ppm.

EXAMPLE 2223-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-pentan-3-ol

1H NMR(CDCl₃) d 6.87(s,1 H), 6.86(s,2 H), 2.43(s,3 H), 2.28(s,3 H0,2.21(s,3 H), 2.0-2.2(m,2 H), 2.02(s,6 H), 1.7-1.9(m,2 H), 1.69(brs,1 H),0.8(t,6 H) ppm.

EXAMPLE 2231-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one

The title compound was prepared by reacting1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-onewith BBr₃ or BCl₃ in THF or methylene chloride.

1H NMR (CDCl₃) d 7.04(s,2 H), 7.01(s,1 H), 3.26(m,1 H), 2.24(s,3 H),2.08(s,6 H), 1.80(m,2 H), 1.63(m,2 H), 0.91(t,6 H) ppm.

EXAMPLE 2244-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinamide

To a solution of4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid in anhydrous methylene chloride was added thionyl chloride. Afterstirring for 1 hr. the reaction mixture was concentrated to dryness. Theresidue was dissolved in dry THF and NH3(g) was bubbled in. The reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to give a lightyellow solid. The solid was purified through silica gel columnchromatography using 1% methanol in chloroform as eluent to give thetitle compound as a white solid, mp. 85-88° C. 1H NMR(CDCl₃) d9.69(brs,1 H), 8.01(brs,1 H), 6.87(s,2 H), 6.11(s,1 H), 5.48(brs,1 H),3.31(m,1 H), 2.29(s,3 H), 2.10(s,3 H), 2.07(s,6 H), 1.60(m,4 H),0.95(t,6 H) ppm.

The title compounds of the following Examples 225 through 231 wereprepared by a method analogous to that described in the precedingparagraph, starting with the corresponding nicotinic acid orpyrimidine-5-carboxylic derivative and quenching with an appropriatenucleophile.

EXAMPLE 2254-(1-Ethyl-propylamino)-6,N-dimethyl-2-(2,4,6-trimethyl-phenoxy)-nicotinamide

1H NMR(CDCl₃) d 9.8(brs,1 H), 8.21(brs,1 H), 6.88(s,2 H), 6.11(s,1 H),3.31(m,1 H), 2.92(d,3 H), 2.30(s,3 H), 2.10(s,3 H), 2.07(s,6 H),1.60(m,4 H), 0.95(t,6 H) ppm.

EXAMPLE 2262-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide

1H NMR(CDCl₃) d 9.7(d,1 H), 7.9(brs,1 H), 7.0(s,2 H), 6.2(s,1 H),5.6(brs,1 H), 3.7(m,1 H), 3.66(m, 1 H), 3.54(m, 1 H), 2.07(s,3 H),2.068(s,3 H), 2.06(s,3 H), 1.7(m, 1 H), 1.6(m, 1 H), 0.99(t,3 H) ppm.

EXAMPLE 2272-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid hydrazide

1H NMR(CDCl₃) d 9.15(s,1 H), 7.04(s,2 H), 6.23(s,1 H), 3.6-3.8(m,2 H),3.53(m,1 H), 2.08(s,6 H), 2.05(s,3 H), 2.04(s,3 H), 1.5-1.8(m,2 H), 1.01(t,3 H) ppm.

EXAMPLE 2282-(4-Chloro-2,6-dimethyl-phenoxy)-N-ethyl-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide

1H NMR(CDCl₃) d 9.74(d,1 H), 8.12(s,1 H), 7.05(s,2 H), 6.23(s,1 H),3.5-3.8(m,3 H), 3.43(m,2 H), 2.06(s,9 H), 1.8(brs, 1 H), 1.5-1.7(m,2 H),1.1 9(t,3 H), 1.00(t,3 H) ppm.

EXAMPLE 2292-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6,N-dimethyl-nicotinamide

1H NMR(CDCl₃) d 9.80(d,1 H), 8.12(s,1H), 7.04(s,2 H), 6.22(s,1 H),3.5-3.8(m,3 H), 2.93(d,3 H),2.06(s,9 H), 1.8(brs,1 H), 1.5-1 .7(m,2 H),0.99(t,3 H) ppm.

EXAMPLE 2302-(4-Chloro-2,6-dimethyl-phenoxy)-N-cyclopentyl-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide

1H NMR(CDCl₃) d 9.69(d,1 H), 8.13(d,1 H), 7.04(s,2 H), 6.22(s,1 H),4.35(m,1 H), 3.4-3.8(m,3 H), 2.056(s,9 H), 1.4-2.0(m, 10 H), 0.99(t,3 H)ppm.

EXAMPLE 2312-(4-Chloro-2,6-dimethyl-phenoxy)-N-cyclopropylmethyl-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide

1H NMR(CDCl₃) d 9.71(d,1 H), 8.24(s,1 H), 7.05(s,2 H), 6.23(s,1 H),3.5-3.8(m,3 H), 3.27(t,2 H), 2.08(s,6 H), 2.07(s,3 H), 1.8(brs,1 H),1.5-1.75(m,2 H), 0.99(t,3 H), 0.46(m,2 H), 0.21(m,2 H) ppm.

The title compounds of the following Examples 232 through 236 wereprepared by a method analogous to that described for Example 224.

EXAMPLE 2324-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide

A brown solid, mp. 204-206° C.

EXAMPLE 2334-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxicacid amide

Mp. 174-176° C.; Anal. For C₂₀H₂₈N₄O₂ calc.: C, 67.39; H, 7.92; N,15.72; found: C, 67.90; H, 8.19; N, 14.66. 1H NMR(CDCl₃) d 7.95(s,1 H),6.89(s,2 H), 5.58(s,1 H), 5.4(m,1 H), 2.28(s,3 H), 2.25(s,3 H), 2.15(s,6H), 1.75(m,4 H), 0.96(t,6 H) ppm.

EXAMPLE 2344-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinonitrile

1H NMR(CDCl₃) d 6.85(s,2 H), 6.06(s,1 H), 4.72(d,1 H), 3.36(m,1 H),2.28(s,3 H), 2.17(s,3 H), 2.09(s,6 H), 1.5-1.8(m,4 H), 0.96(t,6 H) ppm.

EXAMPLE 235[4-(1-Ethyl-propoxy)-6-methyl-3-nitro-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine

The title compound was prepared by heating 2-bromo (orchloro)-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridine with2,4,6-trimethylaniline in DMSO at 130° C. The reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas separated, dried and concentrated to give crude material. Thematerial was purified through silica gel column chromatography to givethe title compound as a yellow solid. 1H NMR(CDCl₃) d 8.52(s,1 H),6.92(s,2 H), 6.12(s,1 H), 4.31(m,1 H), 2.32(s,3 H), 2.24(s,3 H),2.18(s,6 H), 1.77(m,4 H0, 1.01(t,6 H) ppm.

EXAMPLE 2364-(1-Ethyl-propoxy-6-methyl-N2-(2,4,6-trimethyl-phenyl(pyridine-2,3-diamine

The title compound was prepared by hydrogenation of the corresponding3-nitro derivative with 10% Pd/C in ethanol at 50 psi. A pale gray solidwas obtained in 97% yield, mp. 73-75° C. 1H NMR(CDCl₃) d 6.89(s,2 H),6.18(s,1 H), 4.22(m,1 H), 3.2(brs,2 H), 2.29(s,3 H), 2.19(s,6 H),1.7(m,4 H), 0.97(t,6 H) ppm.

EXAMPLE 2372-Chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-acetamide

The title compound was prepared by acylation of4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenylypyridine-2,3-diaminewith chloroacetyl chloride, NEt₃ in THF at room temperature. A tan solidwas isolated, mp. 79-82° C. Anal. For C₂₂H₃₀ClN₃O₂ calc. C, 65.41; H,7.49; N, 10.40; found: C, 65.56; H, 7.62; N, 10.98.

EXAMPLE 238N-Butyl-N-ethyl-6-methyl-3-nitro-N-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine

A mixture of butyl-(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-ethyl-amine(700 mg, 2.58 mmol) and 2,4,6-trimethylaniline in DMSO was heated in140° C. oil bath for overnight. An additional 0.75 ml of2,4,6-trimethylaniline was added and the resulting mixture was heatedfor an additional 48 hours. The mixture was quenched with water, brineand extracted 3 times with ethyl acetate. The organic layer wasseparated, dried (MgSO₄) and concentrated to dryness. After silica gelcolumn chromatography purification, the title compound was obtained asan oil.

EXAMPLE 2394-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid

The title compound was prepared by heating2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid andtrimethylaniline in the presence of potassium carbonate and copper inDMF. The desired product was isolated by silica gel columnchromatography using 5% methanol in chloroform as solvent to give a tansolid, mp. 130-135° C.

EXAMPLE 2404-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid methyl ester

A mixture of 2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acidmethyl ester, trimethylaniline, potassium carbonate, copper in DMF washeated at reflux. The mixture was quenched with ammonium chloride andstirred for 20 min, filtered through celite and washed with ethyl,acetate. The filtrate was extracted with ethyl acetate. The organiclayer was separated, dried and concentrated to dryness. The residue waspurified through silica gel column chromatography using 2% methanol inchloroform as eluent to give the title compound as a solid.

1H NMR(CDCl₃) d 8.9(s,1 H), 8.0(d,1 H), 6.91(s,2 H), 5.79s,1 H),3.92(s,3 H), 3.37(m,1 H), 2.30(s,3 H), 2.17(s,3 H), 2.10(s,6 H),1.5-1.7(m,4 H), 0.96(t,6 H) ppm.

EXAMPLE 241N4-(1-Ethyl-propyl)-3,6dimethyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine

The title compound was prepared by reduction of4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic acid with 1 M of lithium aluminiumhydride in diethyl ether and aluminium trichloride at reflux. 1HNMR(CDCl₃)6.9(s,2 H), 6.0(s,1 H). 5.4(brs,1 H), 3.6(d,1 H), 3.3(m,1 H),2.32(s,3 H), 2.2(s,3 H), 2.15(s,6 H), 1.4-1.7(m,4 H), 1.0(t,6 H) ppm.

EXAMPLE 2422-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylaminoypyridin-3-ylmethyl]-malonicacid dimethyl ester

Mp. 136-138° C.; Anal. For C₂₆H₃₇N₃O₄¾H₂O calc.: C,66.57; H, 8.27; N,8.96; found: C, 66.67; H, 7.95; N, 8.88.

EXAMPLE 243[2-(4-Bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl-methanol

The title compound was prepared by reduction of the correspondingnicotinic acid derivative with BH₃.DMS in THF at reflux. Standardwork-up procedure to give the title compound as a white foam. 1HNMR(CDCl₃) 7.15(s,2 H), 6.2(brs,1 H), 5.92(s,1 H), 4.479m,1 H), 4.43(s,2H), 3.25(m,1 H), 2.17(s,3 H), 2.10(s,6 H), 1.58(m,2 H), 1.47(m,2 H),0.90(t,6 H) ppm.

EXAMPLE 244N2-(2,4-Dichloro-phenyl)-N4-(1-ethyl-propyl)-3,6-dimethyl-pyridine-2,4-diamine

The title compound was prepared by a method analogous to that describedfor Example 146. 1H NMR(CDCl₃) d 7.79(dd,1 H), 7.30(d,1 H), 7.10(dd,1H), 6.53(brs,1 H), 6.13(s,1 H), 3.79(d,1 H), 3.2-3.4(m,1 H), 2.36(s,3H), 1.92(s,3 H), 1.4-1.6(m,4 H), 0.93(t,6 H) ppm.

EXAMPLE 245[2-(2,4-Dichloro-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol

The title compound was prepared by reduction of the correspondingnicotinic acid derivative with BH₃.DMS in THF at reflux. 1H NMR(CDCl₃) d7.22(d,1 H), 7.07(d,1 H), 7.00(d,1 H), 6.10(s,1 H), 5.7(brs,1 H),4.4(s,2 H), 3.3 (m,1 H), 2.35(s,3 H), 2.02(s,3 H), 1.4-1.6(m,4 H),0.92&0.91 (two sets of t,6 H) ppm.

EXAMPLE 2462-[6-Methyl-3-nitro-2-(2,4,6-trimethyl-phenylamino)-pyridin-4-ylamino]-butan-1-ol

The title compound was prepared by heating2-[6-methyl-3-nitro-2chloro-pyridin-4-ylamino]-butan-1-ol withtrimethylaniline in DMSO at 130° C. 1H NMR(CDCl₃) d 9.38(brs,1 H),6.93(s,3 H), 3.7-3.8(m,3 H), 2.30(s,3 H), 2.12(s,6 H), 1.8(m,1 H),1.65(m,1 H), 1.02(t,3 H) ppm

EXAMPLE 2472-[4-(1-Ethyl-propylamino-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-5-yl]-propionicacid ethyl ester

1H NMR(CDCl₃) d 6.85(s,2 H,1 H), 4.49(q,1 H), 4.04.2(m,3 H), 2.289s,3H0, 2.20(s,3 H), 2.06(s,6 H), 1.4-1.7(m,4 H), 1.44(d,3 H), 1.21(t,3 H),0.93(t,3 H), 0.87(t,3 H) ppm.

EXAMPLE 248[3-Aminomethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine

The title compound was prepared by a method analogous to that describedfor Example 188. mp. 117-119° C.; Anal. For C₂₁H₃₁N₃O. ⅓H₂O calc.:C,72.58; H, 9.18; N, 12.09; found: C, 72.93; H, 9.28; N, 12.02.

The following title compounds of Examples 249-251 were prepared byreacting[4-(1-ethyl-propylamino)-6-methyl-2-(4-halo-2,6-dimethyl-phenoxy)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with potassium cyanide in DMSO at room temperature.

EXAMPLE 249(2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-acetonitrile

1H NMR(CDCl₃) d 7.2(s,2 H), 6.1(S,1 H), 3.82(d,1 H), 3.7(s,2 H),3.34(m,1 H), 2.1(s,3 H), 2.03(s,6 H), 1.45-1.7(m,4 H), 0.99(t,6 H) ppm.

EXAMPLE 250[2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-acetonitrilehydrogen chloride

1H NMR(CDCl₃) d 7.08(s,2 H), 6.2(s,1 H), 4.92(d,1 H), 3.45(m,1 H),2.71(s,3 H), 2.549m,2 H), 2.14(s,6 H), 1.7(m,2 H), 1.40-1.6(m,4 H),0.95(t,6 H) ppm.

EXAMPLE 251[6-(1-Ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine

MP. 149-151° C., Anal. For C₂₀H₂₆N₄O calc.: C, 72.81; H, 8.68; N, 13.41;found: C, 72.70; H, 8.86; N, 13.14

EXAMPLE 2522-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

The title compound was prepared by heating the corresponding nicotinicacid derivative at 160-170° C. oil bath. 1H NMR (CDCl3) d 7.05(s,2 H),6.09(s,1 H), 5.35(s,1 H), 4.43(s,1 H), 3.68(m,1 H), 3.64(m,1 H),3.29(m,1 H), 2.30(s,3 H), 2.09(s,6 H), 1.60(m,1 H), 1.47(m,1 H),0.89(t,3 H) ppm.

EXAMPLE 253[3-Aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-yl]-(1-chloromethyl-propyl)-amine

The title compound was prepared by reacting[2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-pyridin-4-(S)-ylamino]-butan-1-olwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with NH₃(g) at room temperature. After standard workupprocedure and silica gel column chromatography, the title compound wasobtained. 1H NMR(CDCl₃) d 7.00(s,2 H), 6.3(brs,1 H), 6.07(s,1 H),4.0-4.2(m,2 H), 3.9(brs,2 H), 3.5-3.8(m,3 H), 2.12(s,3 H), 2.03(s,6 H),1.6-1.9(m,2 H), 1.00(t,3 H) ppm

The following title compounds of Examples 254 and 255 were prepared byreacting [2-(2-(4-chloro-2,6-dimethyl-phenoxy>3-pyridin-4-(S)ylamino]-butan-1-ol with thionyl chloride in benzene,concentrated to dryness, followed by reacting with an appropriate aminein THF at room temperature. After standard workup procedure and silicagel column chromatography, the title compound was obtained.

EXAMPLE 2542-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-methylaminomethyl-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.01(s,2 H), 6.14(s,1 H), 4.55(brs,1 H), 3.6-3.8(m,2 H),3.4(m,1 H), 2.6(s,3 H), 2.11 (s,3 H), 2.02(brs,6 H), 1.65(m,2 H),0.97(t,3 H)ppm.

EXAMPLE 2552-[3-Aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 6.999s,2 H), 6.10(s,1 H), 4.4.00(Abq,2 H), 3.5-3.75(m,2H), 3.4(m, 1 H), 2.73(brs,4 H), 2.08(s,3 H), 2.00(s,6 H), 1.58(m,4 H),0.94(t,3 H) ppm.

The title compounds of the following Examples 256 through 262 wereprepared by bromination or chlorination of2-[2-(substituted-phenoxy)-6-methyl-pyridin-4-alkylamine with NBS or NCSin methylene chloride or chloroform at room temperature.

EXAMPLE 256[3-Bromo-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine

1H NMR(CDCl₃) d 6.85(s,2 H), 6.04(s,1 H), 4.62(d,1 H), 3.33(m,1 H),2.27(s,3 H), 2.13(s,3 H), 2.08(s,6 H), 1.5-1.7(m,2 H), 0.95(t,3 H) ppm.

EXAMPLE 2572-[3,5-Dibromo-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.02(s,2 H), 4.34(m,1 H), 3.6-3.8(m,2 H), 2.30(s,3 H),2.05(s,6 H), 1.5-1.8(m,2 H), 0.98(t,3 H) ppm.

EXAMPLE 2582-[3-Bromo-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.05(s,2 H), 5.62(s,1 H), 4.86(d,1 H), 3.55-3.7(m,2 H),3.3(m,1 H), 2.428(s,3 H), 2.09(s,6 H), 1.4-1.7(m,3 H), 0.91(t,3 H) ppm.

EXAMPLE 2592-[3-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.02(s,2 H), 6.14(s,1 H), 4.81(d,lH), 3.6-3.8(m,2 H),3.45(m,1 H), 2.12(s,3 H), 2.08(s,6 H), 1.5-1.8(m,2 H), 1.00(t,3 H) ppm.

EXAMPLE 2602-[3-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.02(s,2 H), 6.18(s,1 H), 4.76(d,1 H), 3.6-3.8(m,2 H),3.45(m,1 H), 2.13(s,3 H), 2.07(s,6 H), 1.5-1.8(m,2 H), 0.99(t,3 H) ppm.

EXAMPLE 2612-[3,5-Dichloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.03(s,2 H), 4.34(m,1 H), 3.6-3.8(m,2 H), 2.40(s,3 H),2.05(s,6 H), 1.5-1.8(m,2 H), 0.99(t,3 H) ppm.

EXAMPLE 2622-[3-Chloro-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 7.05(s,2 H), 5.66(s,1 H), 4.86(brs,1 H), 3.5-3.8(m,2 H),3.3(m,1 H), 2.38(s,3 H), 2.09(s,6 H), 1.4-1.7(m,3 H), 0.91(t,3 H) ppm.

EXAMPLE 2632-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-yl)-6-methyl-nicotinonitrile

The title compound was prepared by reacting with2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid with triphosgene/NEt₃ in THF. 1H NMR(CDCl₃) d 7.18(s,1 H), 7.06(s,2H), 5.00(m,1 H), 4.64(t,1 H), 4.23(dd,1 H), 2.339s,3 H), 2.08(s,6 H),1.5-1.8(m,2 H), 0.949t,3 H) ppm.

EXAMPLE 2642-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinicacid

1H NMR(CDCl₃) d 8.3(brs,1 H), 6.5(m,3 H), 6.26(s,1 H), 4.66(m,1 H),3.92(s,3 H), 3.85(s,3 H), 3.66(m,2 H), 3.43(s,3 H), 2.52(s,3 H), 1.91(m,2 H), 1.07(t,3 H) ppm.

EXAMPLE 2654-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carbonitrile

1H NMR(CDCl₃) d 6.92(s,2 H), 6.45(s,1 H), 5.22(m,1 H), 2.29(s,6 H),2.16(s,6 H), 1.70(m,4 H), 0.93(t,6 H) ppm.

EXAMPLE 266N-(1-Ethyl-propyl)-2,5-dimethyl-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine

1H NMR(CDCl₃) d 8.9(s,1 H), 6.85(s,2 H), 4.95(d,1 H), 4.21(m,1 H),2.5(s,3 H). 2.25(s,3 H), 2.13(s,6 H), 1.4-1.7(m,4 H), 1.3(s,3 H),0.85(t,6 H) ppm

EXAMPLE 2675-Chloro-N4-(1-ethyl-propyl)-2-methyl-N6-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine

1H NMR(CDCl₃) d 6.85(s,2 H), 6.0(s,1 H), 4.D(m,1 H), 4.2(m,1 H), 2.3(s,3H), 2.22(,3 H), 2.17(s,6 H), 1.4-1.70(m,4 H), 0.97(t,6 H) ppm.

EXAMPLE 2685-Bromo-N-(1-ethyl-propyl)-2-methyl-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine

MP. 117-119° C., Anal. For C₁₉H₂₁BrN₄ calc.: C, 58.31; H, 6.95; N,14.32; found: C, 58.43; H, 7.08; N, 14.23.

EXAMPLE 2694-(1-Ethyl-propylamino)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylicacid

1H NMR(CDCl₃) d 12.2(brs,1 H), 11.1(brs,1 H), 6.84(s,2 H), 4.18(m,1 H),2.38(s,3 H), 2.18(s,3 H), 2.15(s,6 H), 1.56(m,4 H), 0.90(t,6 H) ppm.

EXAMPLE 270[4-(Cyclopropylmethyl-propyl-amino)-2-methyl-6-(2,4,6-trichloro-phenylamino)-pyrimidin-5-yl]-methanol

1H NMR(CDCl₃) d 7.49s,2 H), 4.95(s,2 H), 4.92(s,1 H), 3.28(brs,4 H),2.359s,3 H), 1.54(m,2 H), 0.95(m,1 H), 0.81(t,3 H), 0.44(m,2 H),0.19(m,2 H) ppm.

EXAMPLE 2716-(1-Ethyl-propoxy)-2,N5,N5-trimethyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine

The title compound was prepared by methylation of6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diaminewith lithium bis(trimethylsilyl)amide in THF, followed by quenching withmethyl iodide. 1 H NMR(CDCl₃) d 7.35(s,1 H), 6.90(s,2 H), 5.16(m,1 H),2.73(s,6 H), 2.29(s,3 H), 2.27(s,3 H), 2.18(s,6 H), 1.6-1.8(m,4 H),0.96(t,6 H) ppm.

EXAMPLE 272[5-Bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine

The title compound was prepared by reacting(5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine with 3-pentanol/NaH in THF at refluxovernight. After standard work-up and purification, the title compoundwas obtained as a white solid, mp. 94-96° C. 1H NMR(CDCl₃) d 6.91(s,2H), 6.41(s,1 H), 5.13(m,1 H), 2.29(s,3 H), 2.26(,3 H), 2.17(s,6 H),1.70(m,4 H), 0.95(t,6 H) ppm.

EXAMPLE 2734-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylicacid

To a solution of n-BuLi in THF was added a solution of[5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenylamine in THF at −78° C. After stirring for 10minutes, CO₂(g) was added at −78° C. and stirred at that temperature for1 hour, then gradually warmed to room temperature. The resulting mixturewas quenched with water and adjusted to pH 2 to 3 and extracted withchloroform. The organic layer was separated, dried and concentrated todryness. The residue was purified through silica gel columnchromatography to give the title compound as a solid, mp. 118-120° C.,Anal. For C₂₀H₂₇N₃O₃ calc.: C, 67.20; H, 7.61; N, 11.76; found: C,67.25; H, 7.87; N, 11.48.

EXAMPLE 274[4-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-methanol

To a solution of4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylicacid in dry THF was added BH₃.DMS. The resulting mixture was heated atreflux. The mixture was quenched with dilute HCl and stirred for 30minutes, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to give a crudematerial. The crude material was purified through silica gel columnchromatography to give the title compound as a solid, mp. 121-123° C.,Anal. For C₂₀H₂₉N₃O₂ calc. C, 69.94; H, 8.51; N, 12.23; found: C, 69.73;H, 8.47; N, 11.99.

EXAMPLE 275[6-(1-Ethyl-propoxy)-5-methoxymethyl-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine

The title compound was prepared by reacting[4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-methanolwith NaH, followed by quenching with MeI. 1H NMR(CDCl₃) d 7.0(s,1 H),6.89(s,2 H), 5.12(m,1 H), 4.62(s,2 H), 3.33(s,3 H), 2.28(s,3 H0,2.27(s,3 H), 2.14(s,6 H), 1.66(m,4 H), 0.91(t,6 H) ppm.

EXAMPLE 276(5-Aminomethyl-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine

To a solution of[4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-methanolin anhydrous methylene chloride was added thionyl chloride. Afterstirring for 1 hour, the reaction mixture was concentrated to dryness.The residue was dissolved in dry THF and NH₃(g) was bubbled in. Thereaction mixture was quenched with water and extracted with ethylacetate. The reaction was worked-up and purified by standard procedureto give the title compound.

1H NMR(CDCl₃) d 8.50(s,1 H), 6.88(s,2 H), 5.08(m,1 H), 3.97(s,2 H),2.279s,3 H), 2.25(s,3 H), 2.159s,6 H), 1.74(brs,2 H), 1.65(m,4 H),0.91(t,6 H) ppm.

EXAMPLE 2777-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-2-ylamine

The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diaminewith BrCN in acetonitrile at room temperature overnight.

The mixture was quenched with water and adjusted to pH 8.0 withsaturated sodium bicarbonate and extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to give crudematerial. The material was purified through silica gel columnchromatography to give the title compound as a white solid, mp. 159-161°C. 1H NMR(CDCl₃) d 7.05(s,2 H), 6.5(s,1 H), 4.6(m,1 H), 4.3(m,2 H),2.45(s,3 H), 2.35(s,3 H), 2.0(s,6 H), 1.7(m,4 H), 1.0(t,6 H) ppm.

EXAMPLE 278 7-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridine

A mixture of4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine,trimethyl orthoformate, p-toluenesulfonic acid monohydrate in toluenewas heated at reflux using Dean-Stark apparatus for 24 hours. Themixture was heated at reflux overnight. The mixture was quenched withwater, sat. NaHCO₃, extracted with ethyl acetate. The organic layer wasseparated, dried (MgSO₄) and concentrated to dryness. Afterpurification, the title compound was isolated. Anal. For C₂₁H₂₉N₃O.¼H₂Ocalc. C, 73.76; H, 8.10; N, 12.29; found: C, 73.22; H, 7.96; N, 12.42.

EXAMPLE 2797-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diaminewith triphosgene, NEt₃ in THF at room temperature. A white solid wasisolated, mp. 184-186° C. Anal. For C₂₁H₂₇N₃O₂ calc. C, 71.36; H, 7.70;N, 11.89; found: C, 71.09; H, 7.75; N, 11.63.

EXAMPLE 2807-(1-Ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

The title compound was prepared by reacting7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one with lithium bis(trimethylsilyl)amide, followed byquenching with methyl iodide. Mp. 151-153° C. Anal. For C₂₂H₂₉N₃O₂. ¼H₂Ocalc. C, 71.03; H, 7.99; N, 11.30; found: C, 71.29; H, 8.01; N, 11.03.

EXAMPLE 281 (1-Ethyl-propyl[-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amine

A mixture ofN-4-(1-ethyl-propyl)-6-methyl-N-2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine(250 mg, 0.77 mmol) , trimethyl orthoformate (0.081 g, 0.766 mmol),p-toluenesulfonic acid monohydrate (0.01 g) in benzene was heated atreflux using Dean-Stark apparatus for 24 hours. Benzene was removed andtoluene was added and an excess of trimethyl orthoformate (0.084 ml) wasadded to the reaction mixture. The mixture was heated at refluxovernight. The mixture was quenched with water, sat. NaHCO₃, extractedwith ethyl acetate. The organic layer was separated, dried (MgSO₄) andconcentrated to dryness. After purification, the title compound wasisolated as a white crystal, mp 78-80° C.

EXAMPLE 282 [2,5-Dimethyl-3-(2,4,6-trimethyl-phenyl )-3H-imidazo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine

A mixture ofN-4-(1-ethyl-propyl)-6-methyl-N-2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine(250 mg, 0.77 mmol), trimethyl orthoacetate (0.184 g, 1.532 mmol),p-toluenesulfonic acid monohydrate (0.01 g) in toluene was heated atreflux using Dean-Stark apparatus for 3 hours. The mixture was quenchedwith water, brine, extracted with ethyl acetate. The organic layer wasseparated, dried (MgSO₄) and concentrated to dryness. Afterpurification, the title compound was obtained as a white crystal, mp101-103° C. Anal. For C₂₂H₃₀N₄ calc. C, 75.39; H, 8.63; N, 15.98; found,C, 75.44; H. 8.95; N, 15.95.

EXAMPLE 283 N7-(1-Ethyl-propyl)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridine-2,7-diamine

The title compound was prepared by reactingN4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triaminewith BrCN in acetonitrile at room temperature overnight. The mixture wasquenched with water and adjusted to pH 8.0 with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic layer wasseparated, dried and concentrated to give crude material. The materialwas purified through silica gel column chromatography to give the titlecompound as a brown solid, mp. 158-160° C.; Anal. For C₂₁H₂₉N₅ ¼H₂Ocalc. C, 70.85; H, 8.35; N, 19.67; found: C, 71.07; H, 8.30; N, 19.63.

EXAMPLE 2846-(1-Ethyl-propylamino)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one

The title compound was prepared by methylation of6-(1-ethyl-propylamino)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-onewith lithium bis(trimethylsilyl)amide in THF, followed by quenching withmethyl iodide. 1H NMR(CDCl₃) d 6.98(s,2 H), 4.45(d,1 H), 4.3(m,1 H),3.7(s,3 H), 2.4(s,3 H), 2.3(s,3 H), 2.1(s,6 H), 1.5-1.8(m,4 H), 1.0(t,6H) ppm.

EXAMPLE 2856-(1-Ethyl-propoxy)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one

The title compound was prepared by methylation of6-(1-Ethyl-propoxy)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one with lithiumbis(trimethylsilyl)amide in THF, followed by quenching with methyliodide. 1H NMR(CDCl₃) d7.00(s,2 H), 5.31(m,1 H), 3.66(s,3 H), 2.479s,3H), 2.33(s,3 H), 2.06(s,6 H), 1.79(m,4 H), 1.01(t,6 H) ppm.

EXAMPLE 286[2-(4-Methoxy-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propylyamine

1H NMR(CDCl₃) d 7.71(d,1 H), 6.57(s,2 H), 6.21(s,1 H), 3.76(s,3 H),3.59(m,1 H), 3.48(m,1 H), 3.45(m,1 H), 3.37(s,3 H), 2.13(s,3 H),2.08(s,6 H), 1.6-1.8(m,4 H), 0.86(t,3 H) ppm.

EXAMPLE 287(1-Ethyl-propyl)-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

1H NMR(CDCl₃) d 6.64(s,2 H), 6.12(s,1 H), 3.82(s,3 H), 3.36(m,1 H),2.26(s,3 H), 2.13(s,6 H), 2.10(s,3 H), 1.5-1.8m,4 H), 0.99(t,6 H).

EXAMPLE 2882-[2-(4-Methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-butan-1-ol

1H NMR(CDCl₃) d 6.64(s,2 H), 6.13(s,1 H), 4.10(m,1 H), 3.76(s,3 H),3.7-3.8(m,21 H), 3.57(m,1 H), 2.21(s,3 H), 2.19(s,6 H), 2.12(s,3 H),1.6-1.8(m,2 H), 1.04(t,3 H) ppm.

EXAMPLE 289sec-Butyl-[3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-yl]-amine

1H NMR(CDCl₃) d 6.64(s,2 H), 6.13(s,1 H), 4.51(d,1 H), 3.92(s,3 H),3.82(s,3 H), 3.469m,1 H), 2.18(s,3 H), 2.15(s,6 H), 1.60(m,2 H),1.26(d,3 H), 1.00(t,3 H) ppm.

EXAMPLE 2902-(4-Chloro-2,6-dimethyl-phenoxy)-4-(4-ethyl-oxazolidin-3-yl)-3,6-dimethyl-pyridine

1H NMR(CDCl₃) d 7.07(s,2 H), 6.36(s,1 H), 4.98(m,1 H), 4.78(m,1 H),4.23(m,1 H), 3.83(m,1 H), 3.71(m,1 H), 2.28(s,3 H), 2.20(s,3 H),2.09(s,6 H), 1.81(m,1 H), 1.58(m,1 H), 0.98(t,3 H) ppm.

EXAMPLE 2914-(4-Ethyl-oxazolidin-3-yl)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

1H NMR(CDCl₃) d 6.65(s,2 H), 6.36(s,1 H), 4.98(m,1 H), 4.77(m,1 H),4.23(m,1 H), 3.83(s,3 H), 3.71(m,1 H), ), 2.29(s,3 H), 2.22(s,3 H),2.119(s,6 H), 1.82(m,1 H), 1.56(m,1 H), 0.99(t,3 H) ppm

EXAMPLE 2932-(4-Methoxy-2,6-dimethyl-phenoxy)-N%4&-(1-methoxymethyl-propyl)-6-methyl-pyridine-3,4-diamine

1H NMR(CDCl₃) d 6.64(s,2 H), 6.16(s,1 H), 4.3(m,1 H), 3.82(s,3 H),3.6-3.8(m,2 H), 3.42(s,3 H), 3.2(brs,2 H), 2.18(s,3 H), 2.13(s,6 H),1.6-1.8(m,2 H), 1.03(t,3 H) ppm.

EXAMPLE 2943-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-pentan-2-ol

1H NMR(CDCl₃) d 7.01(s,2 H), 6.16(s,1 H), 5.19(d,1 H), 4.94(m,2 H),3.88(m,1 H), 3.27(m,1 H), 2.11(s,3 H), 2.05(s,6 H), 1.73(m,1 H),1.57(m,1 H), 1.24(d,3 H), 0.97(t,3 H)ppm.

EXAMPLE 2952-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.63(d,1 H), 7.01(s,2 H), 5.90(s,1 H), 3.95(m,1 H),3.90(s,3 H), 2.08(s,3 H), 2.05(s,3 H), 2.03(s,6 H), 1.8-2.0(m,2 H),1.00(t,3 H) ppm.

EXAMPLE 2963-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxymethyl-6-methyl-pyridin-4-ylamino]-pentan-2-ol

1H NMR(CDCl₃) d 7.08(s,2 H), 6.21(s,1 H), 5.40(brs,1 H), 4.83(q,2 H),3.91(m,1 H), 3.40(s,3 H), 3.33(m,1 H), 2.20(s,3 H), 2.10(s,6 H),1.78(m,1 H), 1.58(m,1 H), 1.29(d,3 H), 1.01(t,3 H) ppm.

EXAMPLE 2973-[2-(4-Methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pentan-2-ol

1H NMR(CDCl₃) d 6.66(s,2 H), 6.27(s,1 H), 4.05(m,1 H), 3.82(s,3 H),3.38(m,1 H), 2.35(s,3 H), 2.21(s,3 H), 2.14(s,6 H), 1.6-1.9(m,2 H),1.30(m,3 H), 1.01(t,3 H)ppm.

EXAMPLE 2984-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

1 H NMR(CDCl₃) d 8.01(d,1 H), 6.58(s,2 H), 6.06(s,1 H), 3.85(s,3 H),3.77(s,3 H), 2.10(s,3 H), 2.07(s,6 H), 1.21(d,3 H0, 0.97(t,3 H) ppm.

EXAMPLE 2992-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-2-methyl-propylamino)-6-methyl-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.28(d,1 H), 7.06(s,2 H), 6.32(s,1 H), 3.92(s,3 H),3.41(m,1 H), 2.14(s,3 H), 2.12(s,6 H), 1.91(m,1 H), 1.44(m,1 H),1.33(s,3 H), 1.30(s,3 H0, 0.99(s,3 H) ppm.

EXAMPLE 3004-(1-Hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.13(d,1 H), 6.63(s,2 H), 6.21(s,1 H), 3.91(s,3 H0,3.82(s,3 H0, 3.81(m,2 H), 3.59(m,1 H), 2.16(s,3 H), 2.12(s,6 H),1.6-1.859m,2 H), 1.05(t,3 H) ppm.

EXAMPLE 3012-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.25(d,1 H), 7.02(s,2 H), 6.30(s,1 H), 3.85(s,3 H),3.6-3.9(m,3 H), 2.5-2.7(m,2 H), 2.14(s,3 H), 2.10(s,3 H), 2.06(s,6 H),1.8-2.1(m,2 H)ppm.

EXAMPLE 3012-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.25(d,1 H), 7.01(s,2 H), 6.05(s,1 H), 4.11(m,1 H),3.9-4.1(m,2 H), 3.8-3.9(m,1 H), 3.86(s,3 H), 3.73(m,1 H), 2.2-2.4(m,1H), 2.11(s,3 H), 2.05(s,6 H), 1.95(m,1 H) ppm.

EXAMPLE 302 {3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxycarbonyl-6-methyl-pyridin-4-ylamino]-4-hydroxy-butyl)-dimethyl-sulfoniumiodide

1H NMR(CD₃OD) d 7.11(s,2 H), 6.61(s,1 H), 4.00(m,1 H), 3.86(s,3 H),3.6-3.9(m,3 H), 2.95(d,6 H), 2.5-2.7(m,2 H), 2.22(s,3 H), 2.07(s,6 H),1.8-2.1(m,2 H)ppm.

EXAMPLE 3034-(1-Hydroxymethyl-3-methylsulfanyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.15(d,1 H), 6.58(s,2 H), 6.28(s,1 H), 3.85(s,3 H),3.76(s,3 H), 3.6-3.9(m,3 H), 2.5-2.7(m,2 H), 2.12(s,3 H), 2.09(s,3 H),2.07(s,6 H), 1.8-2.1(m,2 H)ppm.

EXAMPLE 3044-(1-Hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

1HNMR(CDCl₃) d 9.84(d,1 H), 8.31(m,1 H), 6.66(s,2 H), 6.29(s,1 H),3.81(s,3 H), 3.5-3.9(m,3 H), 2.98(d,3 H), 2.15(s,3 H), 2.12(s,6 H),1.6-1.8(m,2 H), 1.05(t,3 H)ppm.

EXAMPLE 3054-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

1H NMR(CDCl₃) d 9.77(brs,1 H), 8.22(brs,1 H), 6.61(s,2 H), 6.11(s,1 H),3.78(s,3 H), 3.45(m,1 H), 2.93(d,3 H), 2.10(s,3 H), 2.07(s,6 H),1.5-1.7(m,2 H), 1.23(m,3 H), 0.98(t,3 H)ppm.

EXAMPLE 3062-(4-Methoxy-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester

1H NMR(CDCl₃) d 8.28(d,1 H), 6.63(s,2 H), 6.09(s,1 H), 4.15(m,1 H),3.98-4.1(m,2 H), 3.8-3.98(m,1 H), 3.90(s,3 H), 3.81(s,3 H), 3.76(m,1 H),2.32-2.36(m,1 H), 2.19(s,3 H), 2.11(s,6 H), 1.95(m,1H) ppm.

EXAMPLE 3074-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinamide

1H NMR(CDCl₃) d 9.74(ds,1 H), 8.05(brs,1 H), 6.65(s,2 H), 6.16(s,1 H),5.55(brs,1 H), 3.83(s,3 H), 3.51 (m,1 H), 2.16(s,3 H), 2.12(s,6 H),1.5-1.7(m,2 H), 1.26(d,3 H), 1.02(t,3 H)ppm.

Preparation A

(6-Chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine

A mixture of 2,5-dimethyl-4,6-dichloropyrimidine (1.77 g, 10 mmol) andtrimethylaniline (2.70 g, 20 mmol) in 5 ml of DMSO was heated in an oilbath of 160° C. for 4 hours. The mixture was quenched with water andextracted with ethyl acetate. The organic layer was separated, dried andconcentrated to give the crude material. After silica gel columnpurification, and titration with hexane, white crystals (790 mg) wereobtained; high MS calc, 275.1185, found 275.11667; IR(KBr) 3290, 3240,2900, 1540 cm-1. 1H NMR (CDCl₃) δ 6.91 (s, 2 H), 5.85 (s, 1 H), 2.33 (s,3 H), 2.87 (s, 3 H), 2.24 (s, 3 H), 2.12 (s, 6 H) ppm.

Preparation B

(6-Chloro-2,5-dimethylpyrimidin-4-ylymethyl-(2,4,6-trimethylphenyl)-amine

A solution of(6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine (276mg, 1 mmol) in dry THF (2 ml) was treated with sodium hydride (60% inoil, 60 mg, 1.5 mmol) at room temperature. After stirring for 2 minutes,an excess of methyl iodide (0.5 ml) was added and the resulting mixturewas stirred at room temperature for 20 minutes. The mixture was quenchedwith saturated ammonium chloride and extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to give a paleyellow solid (255 mg). ¹H NMR (CDCl₃) δ 6.85 (s, 2 H), 3.26 (s, 3 H),2.50 (s, 3 H), 2.27 (s, 3 H), 2.03 (s,. 6 H), 1.39 (s, 3 H) ppm.

Preparation C

4-Chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine

A solution of 2,4,6-trimethylphenol (2.720 g, 20 mmol) in 60 ml of dryTHF was treated with NaH (60% in oil, 1.200 g, 30 mmol) at roomtemperature. After stirring at room temperature for 15 minutes,2,5-dimethyl-4,6-dichloropyrimidine (3.34 g, 20 mmol) was added and theresulting mixture was heated at reflux for 15 hours. The mixture wasquenched with saturated ammonium chloride and extracted with ethylacetate. The organic layer was dried and concentrated to give 5.4528 gof beige solid. The solid was recrystallized from isopropanol to give5.1345 g of pale yellow solid, mp 86-87° C.; high MS (C₁₅H₁₇ClN₂₀) calc.276.1025, found 276.10359. ¹H NMR (CDCl₃) δ 6.87 (s, 2 H), 2.37 (s, 6H), 2.28 (s, 3 H), 2.01 (s, 6 H) ppm.

Preparation D

2,4-Dichloro-3,6-dimethylpyridine

A mixture of 2,4-dihydroxy-3,6-dimethylpyridine (2.86 g, 20.58 mmol),POCl₃ (15 ml) and N,N-diethylaniline (3.6 ml, 22.64 mmol) was heated atreflux for 3 hours. The mixture was cooled, poured into ice water andextracted with diethyl ether. The organic layer was dried andconcentrated to give 3.02 g of the crude material. After silica gelcolumn chromatography using chloroform as eluent, 1.3102 g of the titlecompound was obtained as a yellow oil. ¹H NMR (CDCl₃) δ 7.07 (s, 1 H),2.43 (s, 3 H), 2.39 (s, 3 H) ppm.

Preparation E

4-Chloro-3,6-dimethyl-2-(2,4,6-trimethyl-phenyoxy)-pyridine

A solution of 2,4,6-trimethylphenol (450 mg, 3.31 mmol) in 2 ml of DMSOwas treated with NaH (60% in oil, 180 mg, 4.5 mmol). After 5 min,2,4-Dichloro-3,6-dimethyl-pyridine (528 mg, 3 mmol) was added. Themixture was heated in the oil bath of 130° C. for 6 hours. The mixturewas quenched with water and extracted with EtOAc. The organic layer wasdried and concentrated to give 812.5 mg of crude material with tworegioisomers. After silica gel column chromatography using 1:1 ofCHCl₃:hexane as eluent, the title compound was isolated as whitecrystals (141 mg), mp 57-62° C.; high MS for C₁₆H₁₈ClNO: calc, 275.1072,found 275.70172; IR(KBr) 2951, 2920, 1592, 1564 cm-1; ¹H NMR (CDCl₃) δ6.87 (s, 2 H), 6.77 (s, 1 H), 2.39 (s, 3 H), 2.29 (s, 3 H), 2.18 (s, 3H), 2.03 (s, 6 H) ppm. The regiochemistry was determined by X-raystructural analysis of the undesired regioisomer,2-chloro-3,6-dimethyl-4-(2,4,6-trimethyl-phenyoxy)-pyridine.

To a solution of4-chloro-2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxide (34mg) in 1 ml dry methylene chloride was added 2M PCl₃ in methylenechloride (0.022 ml). After addition, the mixture was heated at refluxfor 0.5 hours, cooled and concentrated to dryness. The residue waspoured into ice-water and extracted with methylene chloride. The organiclayer was washed with brine, neutralized with sat. sodium carbonate,dried and concentrated to give 47 mg of the crude material. The crudematerial was crystallized out upon standing to give 31 mg (95%) of whitecrystals of the title compound.

Preparation F

(6-Chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-acetonitrile

To a solution of mesitylacetonitrile (0.900 g, 5.65 mmol) in 8 ml dryTHF was added sodium hydride (60% in oil, 0.250 g, 6.21 mmol) and themixture was stirred at room temperature for 40 minutes.2,5-Dimethyl-4,6-dichloropyrimidine (1.000 g, 5.65 mmol) was added andthe resulting mixture was heated at reflux for 5 hours. The mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas dried and concentrated to give 1.800 g of a yellow oil. The oilresidue was purified through silica gel column chromatography using 10%ethyl acetate in hexane as eluent to give 0.986 g (58.3%) of the titlecompound as a white solid, mp 100-102° C. ¹H NMR (CDCl₃) δ 6.86 (s, 2H), 5.60 (s, 1 H), 2.69 (s, 3 H), 2.25 (s, 3 H), 2.18 (s, 6 H), 1.92 (s,3 H) ppm.

Preparation G

2-(6-Chloro-2,5-dimethylpyrimidin-4-yl)-2-(2,4,6-trimethylphenyl)-propionitrile

A solution of(6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-acetonitrile(0.250 g, 0.834 mmol) in 4 ml of dry THF was cooled to −78° C. andtreated with lithium bistrimethylsilylamide (1.0 M in THF, 0.92 ml) andstirred at that temperature for 45 minutes. Methyl iodide (0.426 g, 3.00mmol) was added. The reaction mixture was gradually warmed to roomtemperature and stirred for 1 hour. The reaction mixture was quenchedwith water and extracted with ethyl acetate. The organic layer was driedand concentrated to give a yellow oil. The oil residue was purifiedthrough silica gel chromatotron using ethyl acetate/hexane (4:6) aseluent to give 161 mg (62%) of yellow solid, mp 181-183° C. ¹H NMR(CDCl₃) δ 6.980 (s, 2 H), 3.45 (s, 3 H), 2.40 (s, 3 H), 2.24 (s, 3 H),2.21 (s, 6 H), 1.25 (s, 3 H) ppm.

Preparation H

4-Hydroxy-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine

A mixture of6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-acetonitrile(1.5 g, 5.0 mmol) and 60 ml of 85% phosphoric acid was heated at refluxfor 2 hours. The mixture was cooled at rt and diluted with water andextracted with chloroform. The organic layer was washed with brine,dried and concentrated to give 1.21 g (95%) of the title compound as awhite solid, mp 260-262° C.

Preparation I

4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine

A mixture of4-hydroxy-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine (1.2 g,4.68 mmol) and POCl₃ (25 ml) was heated at reflux for 1 hour. Themixture was cooled and evaporated to dryness. The residue was pouredinto ice-water and extracted with ethyl acetate. The organic layer waswashed with brine, dried and concentrated to dryness to give 1.24 g(97%) of golden crystals, mp 82-84° C.

Preparation J

The following compounds were prepared by the methods analogous to thatin Preparation C starting with5-substituted-4,6-dichloro-2-methyl-pyrimidine and substituted phenol intetrahydrofuran in the presence of a base (sodium hydride) at thetemperature indicated below.

5tert-Butyl-4-chloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine

The reaction was carried out at reflux in THF to give white crystals, mp70-72° C., ¹H NMR (CDCl₃) δ 6.82 (s, 2 H), 2.28 (s, 3 H), 2.24 (s, 3 H),1.96 (s, 6 H), 1.60 (s, 9H) ppm.

4-Chloro-5-isopropyl-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine

The reaction was carried at reflux in THF to give white crystals, mp68-70° C. ¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 3.60 (m, 1 H), 2.36 (s, 3 H),2.29 (s, 3 H), 2.00 (s, 6 H), 1.43 (s, 3 H), 1.41 (s, 3 H) ppm.

4,5-Dichloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine

The reaction run at room temperature to give white crystals, mp 68-70°C. ¹H NMR (CDCl₃) δ 6.88 (s, 2 H), 2.41 (s, 3 H), 2.29 (s, 3 H), 2.04(s, 6 H) ppm.

4-Chloro-5-bromo-2-methyl-4-(2,4,6-trimethyl-phenoxy)-pyrmidine

The reaction was run at 0° C. to room temperature. ¹H NMR (CDCl₃) δ 6.88(s, 2 H), 2.41 (s, 3 H), 2.29 (s, 3 H), 2.03 (s, 6 H) ppm.

4-Chloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidine-5-carbonitrile

The reaction was run at −40° C. to give yellow crystals, mp 89-91° C. ¹HNMR (CDCl₃) δ 6.89 (s, 2 H), 2.51 (s, 3 H), 2.29 (s, 3 H), 2.04 (s, 6 H)ppm.

Preparation K

2,4-Dichloro-3,6-diemthyl-pyridine 1-oxide

A mixture of 2,4-dichloro-3,6-dimethyl-pyridine (790 mg, 4.49 mmol) and50% m-chloro-perbenzoic acid (1.544 g, 4.49 mmol) in 10 ml of chloroformwas stirred at room temperature for 20 hours. The mixture was quenchedwith water, washed with saturated sodium thiosulfate and saturatedsodium carbonate, brine and extracted with chloroform. The organic layerwas dried and concentrated to give 954 mg of crude material. Thematerial was purified through silica gel to give 662 mg of the titlecompound as a white crystals, mp 131-132° C. ¹H NMR (CDCl₃) δ 7.22 (s, 1H), 2.51 (s, 3 H), 2.47 (s, 3 H) ppm.

Preparation L

The following compounds were prepared by the method analogous to thatdescribed in Preparation K starting with an appropriate2,4-dichloro-pyridine and an oxidizing agent.

2,4-Dichloro-6-methyl-1-oxy-nicotinic acid methyl ester

M.p. 90-91.5° C. ¹H NMR (CDCl₃) δ 7.26 (s, 1 H), 3.98 (s, 3 H), 2.54 (s,3 H) ppm.

(2,4-Dichloro-6-methyl-1-oxy-pyridin-3-yl)methanol

M.p. 188-191° C. ¹H NMR (CDCl₃) δ 7.13 (s, 1 H), 4.87 (d, 2 H), 2.47 (s,3 H), 2.38 (t, 1 H, OH) ppm.

2,4-Dichloro-3,5,6-trimethyl-pyridine 1-oxide

M.p. 146-148° C. ¹H NMR (CDCl₃) δ 2.57 (s, 3 H), 2.49 (s, 3 H), 2.38 (s,3 H)) ppm.

2,4-Dichloro-6-methyl-pyridine 1-oxide

M.p. 100-102° C. ¹H NMR (CDCl₃) δ 7.42 (d, 1 H), 7.22 (d, 1 H), 2.55 (s,3 H) ppm.

Preparation M

4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyridine-1-oxide

To a solution of 2,4,6-trimethylphenol (415 mg, 3.05 mmol) in dry THF(20 ml) was treated with 60% sodium hydride in oil (122 mg, 3.05 mmol)at room temperature. After all H₂ was evolved,2,4-dichloro-3,6-dimethyl-pyridine 1-oxide (585.4 mg, 3.05 mmol) wasadded and the resulting mixture was heated at reflux for 2 hours. Themixture was quenched with saturated ammonium chloride and extracted withethyl acetate. The organic layer was dried and concentrated to drynessto give solid. The solid was recrystallized from pet ether to give 802mg (90%) of the title compound as white crystals, mp 106-107° C. ¹H NMR(CDCl₃) 6 7.04 (s, 1 H), 6.78 (s, 2 H), 2.41 (s, 3 H), 2.36 (s, 3 H),2.22 (s, 3 H), 2.06 (s, 6 H) ppm.

Preparation N

The following compounds were prepared by the method analogous to thatdescribed in Preparation M starting with an appropriate2,4-dichloro-pyridine-1-oxide with an appropriate phenol or thiophenolin the presence of a base (potassium tert-buoxide, sodium hydride, orpotassium hydride) at temperature between room temperature to reflux indry THF.

2-(4-Bromo-2,6-dimethyl-phenoxy)-4-chloro-3,6-dimethyl-pyridine 1-oxide

White crystals, mp 137-139° C. ¹H NMR (CDCl₃) δ 7.12 (s, 2 H), 7.08 (s,1 H), 2.42 (s, 6 H), 2.09 (s, 6 H) ppm.

4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine 1-oxide

¹H NMR (CDCl₃) δ 7.08 (s, 1 H), 6.97 (s, 2 H), 2.42 (s, 6 H), 2.09 (s, 6H) ppm,

4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-1-oxy-nicotinic acidmethyl ester

¹H NMR (CDCl₃) δ 7.04 (s, 1 H), 6.78 (s, 2 H), 3.48 (s, 3 H), 2.52 (s, 3H), 2.22 (s, 3 H), 2.08 (s, 6 H) ppm.

4-Chloro-2,3,5trimethyl-6-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxide

White crystals, mp 132-134° C. ¹H NMR (CDCl₃) δ 6.75 (s, 2 H), 2.47 (s,3 H), 2.38 (s, 3 H), 2.35 (s, 3 H), 2.20 (s, 3 H), 2.04 (s, 6 H) ppm.

4-Chloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxide

White crystals, mp 191-193° C. ¹H NMR (CDCl₃) δ 6.96 (s, 1 H), 6.95 (s,2 H), 2.62 (s, 3 H), 2.32 (s, 3 H), 2.13 (s, 6 H) ppm.

4-Chloro-2-(2,4-dimethyl-phenylsulfanyl)-3,6-dimethyl-pyridine 1-oxidewhite crystals, mp 148-151° C. ¹H NMR (CDCl₃) δ 7.23 (s, 1 H), 7.02 (s,1 H), 6.88 (s, 2 H), 2.46 (s, 3 H), 2.41 (s, 3 H), 2.39 (s, 3 H), 2.27(s, 3 H) ppm.

4-Chloro-2-(2,4,6-trimethyl-phenylsulfanyl)-3,6-dimethyl-pyridine1-oxide

White crystals, mp 132-134° C. ¹H NMR (CDCl₃) δ 7.13 (s, 1 H), 6.91 (s,2 H), 2.46 (s, 3 H), 2.31 (s, 6 H), 2.27 (s, 3 H), 2.10 (s, 3 H) ppm.

Preparation O

The following compounds were prepared by the method analogous to thatdescribed in Preparation E, second paragraph, starting with anappropriate 4-chloro-6-substituted phenoxy-pyridine 1-oxide andphosphorous trichloride.

2-(4-Bromo-2,6-dimethyl-phenoxy)-4-chloro-3,6-dimethyl-pyridine

White crystals. ¹H NMR (CDCl₃) δ 7.22 (s, 2 H), 6.81 (s, 1 H), 2.40 (s,3 H), 2.20 (s, 3 H), 2.05 (s, 6 H) ppm.

4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

White crystals. ¹H NMR (CDCl₃) δ 7.07 (s, 2 H), 6.81 (s, 1 H), 2.41 (s,3 H), 2.20 (s, 3 H), 2.06 (s, 6 H) ppm.

4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methylester

Yellow crystals, mp 122-125° C. ¹H NMR (CDCl₃) δ 6.84 (s, 2 H), 6.82 (s,1 H), 3.94 (s, 3 H), 2.27(s, 3 H), 2.25 (s, 3 H), 2.04 (s, 6 H) ppm.

4-Chloro-2,3,5-trimethyl-(2,4,6-trimethyl-phenoxy)-pyridine

White crystals, mp 101-103° C. ¹H NMR (CDCl₃) δ 6.85 (s, 2 H), 2.39 (s,3 H), 2.28 (s, 3 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 2.01 (s, 6 H) ppm.

4-Chloro-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridine

White crystals, mp 46-48° C. ¹H NMR (CDCl₃) δ 6.92 (s, 2 H), 6.84 (s, 1H), 2.62 (s, 3 H), 2.32 (s, 3 H), 2.13 (s, 6 H) ppm.

4-Chloro-2-(2,4-dimethyl-phenylsulfanyl)-3,6-dimethyl-pyridine

White crystals, mp 148-151° C. ¹H NMR (CDCl₃) δ 7.23 (s, 1 H), 7.02 (s,1 H), 6.88 (s, 2 H), 2.46 (s, 3 H), 2.41 (s, 3 H), 2.39 (s, 3 H), 2.27(s, 3 H) ppm.

4-Chloro-2-(2,4,6-trimethyl-phenylsulfanyl)-3,6-dimethyl-pyridine

White crystals, mp 132-134° C. ¹H NMR (CDCl₃) δ 7.13 (s, 1 H), 6.91 (s,2 H), 2.46 (s, 3 H), 2.31 (s, 6 H), 2.27 (s, 3 H), 2.10 (s, 3 H) ppm.

Preparation P

2-Chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl ester

A mixture of 2,4-dichloro-6-methyl-nicotinic acid methyl ester (2.228 g,10.13 mmol) and 1-ethyl-propyl amine (1.762 g, 20.26 mmol) in DMSO (4ml) was heated at 110° C. for 5 hours, then at room temperatureovernight. The mixture was quenched with water and extracted with ethylacetate. The organic layer was dried and concentratd to give 1.796 g ofcrude material. The crude material was purified through silica gelcolumn chromatography using chloroform to 5% methanol in chloroform aseluent to give 1.167 g (43%) of the title compound as a colorless oil.¹H NMR (CDCl₃) δ 7.14 (brs, 1 H), 6.27 (s, 1 H), 3.86 (s, 3 H), 3.27 (m,1 H), 2.33 (s, 3 H), 1.3-1.6 (m, 4 H), 0.88 (t, 6 H) ppm.

Preparation Q

(2-Chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine

A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (250 mg, 1.21 mmol)and 1-ethyl-propyl amine (105 mg, 1.21 mmol) in DMSO (4 ml) was stirredat room temperature for 15 hours. The mixture was quenched with waterand extracted with ethyl acetate. The organic layer was dried andconcentratd to give 280 mg of yellow oil. The oil was purified throughsilical gel column chromatography using 65% chloroform in hexane aseluent to give 110 mg (35%) of the title compound as a yellow crystal,mp 82-84° C. ¹H NMR (CDCl₃) δ 6.57 (d, 1 H), 6.46 (s, 1 H), 3.39 (m, 1H), 2.42 (s, 3 H), 1.4-1.8 (m, 4 H), 0.94 (t, 6 H) ppm

Preparation R

(6-Chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine

A mixture of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208 mg, 1.00mmol) and 1-ethyl-propyl-amine (87 mg, 1.03 mmol) in 2 ml of dry THF wasstirred at −78° C. for 4 hours. The mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed with brine,dried and concentrated to give a green oil. The oil was purified throughsilica gel column chromatography using chloroform to 1:1hexane/chloroform as eluent to give the title compound (93 mg, 35%). ¹HNMR (CDCl₃) δ 7.50 (brs, 1 H), 4.29 (m, 1 H), 2.51 (s, 3 H), 1.4-1.8 (m,4 H), 0.92 (t, 6 H) ppm.

Preparation S

(6-Chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethyl-pyridin-3-yl)-amine

A solution of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208 mg, 1.00mmol) in 2.5 ml of acetonitrile was treated with2,4,6-trimethyl-3-amino-pyridine (273 mg, 2 mmol) stirred at roomtemperature 2 hours. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried andconcentrated to give red residue. The residue was purified throughsilica gel column chromatography using chloroform to 6% methanol inchloroform as eluent to give the title compound (110 mg, 36%) as anorange oil. ¹H NMR (CDCl₃) δ 8.78 (brs, 1 H), 6.97 (s, 1 H), 2.54 (s, 3H), 2.43 (s, 3 H), 2.40 (s, 3 H), 2.17 (s, 3 H) ppm.

Preparation T

2-Chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid

The title compound was prepared by reaction of2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl esterwith LiOH.H₂O in a mixture of water and dioxane at room temperature. Thedesired product was acidified to pH 3 and extracted with ethyl acetate.The organic layer was dried and concentrated to dryness. The titlecompound was obtained as white crystals after titration with ethylacetate. mp. 164-165° C.; anal. For C₁₂H₁₇Cl₂O₂ cacl. C, 56.14; H, 6.67;N, 10.91; found: C, 56.40; H, 6.53; H, 10.93.

Preparation U

4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxide

To a solution of 2,4,6-trimethylphenol in dry THF was added NaH andstirred at room temperature for 20 minutes. A solution of2,4-dichloro-6-ethyl-3-methyl-pyridine 1-oxide was added and theresulting mixture was heated at reflux for 1.5 hour. The mixture wascooled to room temperature, quenched with water, extracted with ethylacetate. The organic layer was separated, dried and concentrated to givethe title compound which was used directly for the next step reaction.

Preparation V

4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

To a solution of4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxidein methylene chloride was added PCl₃ and the resulting mixture washeated at reflux for 20 min, cooled to rt. The mixture was concentratedto dryness. The residue was worked-up using standard procedure to givethe title compound. After silica gel purification, the title compoundwas prepared as a white solid, mp. 42-44° C. Anal. For C₁₇H20CO calc. C,70.46; H, 6.96; N, 4.83; found, C, 70.35; H, 7.13; N, 4.58.

Preparation W

2-[4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid dimethyl ester

The title compound was prepared by reacting4-chloro-3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridinewith dimethyl malonate/NaH in methanol. The title compound was isolatedas a colorless oil.

Preparation X

4-Chloro-3,6-dimethyl-2-(2,4,6-trimethyl-3-pyridyl)-pyridine

Preparation Y

2-Chloro-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinic acid ethyl ester

1H NMR(CDCl₃) d 6.72(s,1 H), 4.5(m,1 H), 4.4(q,2 H), 3.49(d,2 H),3.31(s,3 H), 2.46(s,3 H), 1.68(m,2 H), 1.34(t,3 H), 0.93(t,3 H) ppm.

Preparation Z

2-Chloro-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinic acid

1H NMR(CDCl₃) d 6.81(s,2 H), 4.51(m,1 H), 3.60(m,2 H), 3.40(s,3 H),2.55(s,3 H), 1.77(m,2 H), 1.02(t,3 H)ppm.

Preparation AA

(2-Chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-methoxymethyl-propyl)-aminemp. 63-65° C., Anal. For C₁₁H16N3O3Cl calc. C, 48.27; H, 5.89, N, 15.35;found C, 48.65; H, 6.03, N, 15.11.

Preparation BB

(5-Bromo-6-chloro-2-methyl-pyrimidin-4-yl)-(2,4-dichloro-phenyl)-amine

Mp. 165-167° C.; Anal. For C11H7BrCl3 calc.: C, 35.95; H, 1.92; N,11.43; found: C, 36.41; H, 1.91; N, 11.05.

Preparation CC

(6-Chloro-2-methyl-pyrimidin-4-yl)-(2,4-dichloro-phenyl)-amine

Mp. 134-136° C.; Anal. For C₁₁H₈Cl₃N₃ calc.: C, 45.79; H, 2.79; N,14.56; found: C, 45.91; H, 2.69; N, 14.50.

Preparation DD

[4-Chloro-6-(1-ethyl-propylamino)-2-methyl-pyrimidin-5-yl]-acetic acidethyl ester

Mp. 78-80° C., anal. For C₁₄H₂₂ClN₃O₂ calc.: C, 56.09; H, 7.40; N,14.02; found: C, 56.31; H, 7.60; N,13.94.

Preparation EE

2-[4-Bromo-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-5-yl-propionicacid ethyl ester

1H NMR(CDCl₃) d 6.86(s,2 H), 4.2-4.359m,2 H), 4.0-4.15(m,1 H), 2.4(s,3H), 2.28(s,3 H), 1.99(s,3 H), 1.97(s,3 H), 1.58(d,3 H), 1.22(t,3 H) ppm.

Preparation FF

2-(4,6-Dibromo-2-methyl-pyriman -5-yl)-propionic acid ethyl ester

1 H NMR(CDCl3)4.36(m,1 H), 4.19(m,2 H), 2.68(s,3 H), 1.549d,3 H),1.22(t,3 H) ppm.

Preparation GG

4-Bromo-3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

1H NMR(CDCl₃) d 6.92(s,1 H), 6.87(s,2 H), 4.00(s,3 H), 2.299s,3 H),2.18(s,3 H), 2.059s,6 H) ppm.

Preparation HH

4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

1H NMR(CDCl₃) d 7.04(s,2 H), 6.97(s,1 H), 2.42(s,3 H), 2.17(s,3 H),2.03(s,6 H) ppm.

Preparation II

4-Bromo-2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridine

1H NMR(CDCl₃) d 7.3(d,1 H), 7.18(d,1 H), 4.0(s,3 H), 2.2(s,3 H),2.15(s,3 H) ppm.

Preparation JJ

4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridine

Anal. For C₁₅H₁₅BrClNO₂ calc.: C, 50.52; H, 4.24; N, 3.93; found: C,50.52; H, 4.37; N, 3.91.

Preparation KK

4-Bromo-2-(4-chloro-2-methoxy-phenoxy)-3-methoxy-6-methyl-pyridine

1H NMR(CDCl₃) d 6.9-7.1(m,4 H), 3.94(s,3 H), 3.71(s,3 H), 2.21s,3 H)ppm.

Preparation LL

4-Bromo-2-(3-chloro-2,6-dimethoxy-phenoxy)-3-methoxy-6-methyl-pyridine

1H NMR(CDCl₃) d 7.17(d,1 H), 6.96(s,1 H), 6.66(d,1 H), 3.97(s,3 H),3.79(s,3 H), 3.70(s,3 H), 2.18(s,3 H) ppm.

Preparation MM

4-Bromo-3-methoxy-6-methyl-2-(2,4,6-trimethoxy-phenoxy)-pyridine

1H NMR(CDCl₃) d 6.90(s,1 H), 6.19(s,2 H), 3.968(s,3 H), 3.80(s,3 H),3.71(s,6 H), 2.18(s,3 H) ppm.

Preparation NN

4-Bromo-3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridine

1H NMR(CDCl₃) d 6.92(s,1 H), 6.60(s,2 H), 3.98(s,3 H), 3.78(s,3 H),2.18(s,3 H), 2.07(s,6 H) ppm.

Preparation OO

4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3-ethoxy-6-methyl-pyridine

1H NMR(CDCl₃) d 7.099s,2 H), 7.00(s,1 H), 4.28(q,2 H), 2.22(s,3 H),2.10(s,6 H), 1.51(t,3 H) ppm.

Preparation PP

4-Bromo-3,6-dimethyl-2-(2,4,6-trimethoxy-phenoxy)-pyridine

1H NMR(CDCl₃) d 6.99(s,1 H), 6.25(s,2 H), 3.86(s,3 H), 3.77(s,6 H),2.47(s,3 H), 2.25(s,3 H) ppm.

Preparation QQ

4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-1-oxy-nicotinic acidmethyl ester

Preparation RR

4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester

1H NMR(CDCl₃) d 7.03(s,2 H), 6.869s,1 H), 3.969s,3 H), 2.259s,3 H),2.05(s,6 H) ppm.

Preparation SS

4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehyde

The title compound was prepared by oxidation of4-chloro-4-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl-methanol withpyridinium chlorochromate in methylene chloride at room temperature. Thedesired product was isolated after column chromatography to give a greensolid (80% yield). 1H NMR(CDCl₃) d 10.66(s,1 H), 6.91(s,3 H), 2.31(s,3H), 2.07(s,3 H) ppm.

Preparation TT

2-(4-Bromo-2,6-dimethyl-phenoxy)-4-chloro-6-methyl-nicotinic acid methylester

mp. 108-110° C.; Anal. For C₁₆H₁₅BrClNO₃ calc., 49.96; H, 3.93; N, 3.64;found: C, 50.07; H, 4.10; N, 3.57.

Preparation UU

4-Chloro-2-(4-chloro-2-methoxy-phenoxy)-6-methyl-1-oxy-nicotinic acidmethyl ester

mp. 117-120° C., Anal. For C₁₅H₁₃NO₅Cl₂ calc.: C, 50.30; H, 3.66; N,3.91; Found: C, 50.41; H, 3.55; N, 4.00.

Preparation VV

4-Chloro-2-(4-chloro-2-methoxy-phenoxy)-6-methyl-nicotinic acid methylester

mp. 92-93° C., Anal. For C₁₅H₁₃NO₄Cl₂ calc.: C, 52.65; H, 3.83; N, 4.09;found: C, 52.34; H, 3.85; N, 4.13.

Preparation WW

[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

1H NMR(CDCl₃) d 7.06(s,2 H), 6.12(s,1 H), 4.3(d,1 H), 3.6-3.8(m,2 H),3.4(m,1 H), 2.16(s,3 H), 2.14(s,3 H), 2.10(s,6 H), 1.5-1.8(m,2 H),1.03(t,3 H), 0.95(s,9 H), 0.09(m,6 H) ppm.

The following compounds were prepared by a method analogous to thatdescribed in Example 160, using an appropriate 4-bromo-2-(substitutedphenoxy)-6-alkyl or alkoxy-pyridine with1-(tert-Butyl-dimethyl-silanyloxymethyl)-propylamine.

Preparation XX

[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[3-methoxy4-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-yl]-amine

1H NMR (CDCl₃) d 6.84(s,2 H), 6.08(s,1 H), 4. 8(d,1 H), 3.88(s,3 H),3.5-3.7(m,2 H), 3.3(m,1 H), 2.27(s,3 H), 2.099s,3 H), 2.07(s,6 H),1.75(m,1 H), 1.55(m,1 H), 0.97(t,3 h), 0.89(s,9 H), 0.04(s,6 H) ppm.

Preparation YY

[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-amine

1H NMR(CDCl₃) d 7.02(s,2 H), 6.10(s,1 H), 4.80(d,1 H), 3.87(s,3 H),3.6-3.7(m,2 H), 3.30(m,1 H), 2.09(s,3 H), 2.08(s,6 H), 1.75(m,1 H),1.55(m,1 H), 0.97(t,3 H), 0.89(s,9 H), 0.03(s,6 H) ppm.

Preparation ZZ

4-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propylamino]-2-(4chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-3-ol

1H NMR(CDCl₃) d 7.01 (s,2 H), 6.15(s,1 H), 4.46(d,1 H), 3.7(m,1 H),3.6(m,1 H), 3.4(m,1 H), 2.09(s,3 H), 2.08(s,6 H), 1.5-1.8(m,2 H),1.06(s,9H), 0.98(t,3 H), 0.24(s,6 H) ppm.

Preparation AAA

[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[3-methoxy-6-methyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine

1H NMR(CDCl₃) d 6.19(s,2 H), 6.09(s,1 H), 3.86(s,3 H), 3.80(s,3 H),3.73(s,6 H), 3.3(m,1 H), 2.16(s,3 H), 1.75(m,1 H), 1.5(m,1 H), 0.95(t,3H), 0.89(s,9 H), 0.04(s,6 H) ppm.

Preparation BBB

4-{4-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propylamino]-3-methoxy-6-methyl-pyridin-2-yloxy}-3,5-dimethyl-benzonitrile

1H NMR(CDCl₃) d 7.40(s,2 H), 6.19(s,1 H), 4.90(brs,1 H), 3.87(s,3 H),3.70(m,2 H), 3.3(m,1 H), 2.19(m,9 H), 1.5-1.8(m,2 H), 1.02(t,3 H),093(s,9 H), 0.09(s,6 H) ppm.

1-28. (cancelled)
 29. A pharmaceutical composition for the treatment of(a) a disorder or condition the treatment of which can be effected orfacilitated by antagonizing CRF or (b) a disorder or condition selectedfrom inflammatory disorders, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; sleep disorders induced bystress; pain perception; mood disorders, mood disorders associated withpremenstrual syndrome, and postpartum depression; dysthemia; bipolardisorders; cyclothymia; chronic fatigue syndrome; stress-inducedheadache; cancer; irritable bowel syndrome, Crohn's disease; spasticcolon; post operative ileus; ulcer; diarrhea; stress-induced fever;human immunodeficiency virus infections; neurodegenerative diseases;gastrointestinal diseases; eating disorder; hemorrhagic stress; chemicaldependencies or addictions; drug or alcohol withdrawal symptoms;stress-induced psychotic episodes; euthyroid sick syndrome; syndrome ofinappropriate antidiuretic hormone; obesity; infertility; head trauma;spinal cord trauma; ischemic neuronal damage; excitotoxic neuronaldamage; stroke; immune dysfunctions; muscular spasms; urinaryincontinence; senile dementia of the Alzheimer's type; multi infarctdementia; amyotrophic lateral sclerosis; hypertension; tachycardia;congestive heart failure; osteoporosis; premature birth; hypoglycemia,and Syndrome X in a mammal or bird, comprising a pharmaceuticallyacceptable carrier and an amount of the following compound that iseffective in the treatment of such disorder or condition:

or a pharmaceutically acceptable salt thereof, wherein A is —CR₇; B is—NR₁R₂, —CR₁R₂R₁₁, —C(═CR₂R₁₂)R₁, —NHCHR₁R₂, —OCHR₁R₂, —SCHR₁R₂,—CHR₂OR₁, —CHR₁OR₂, —CHR₂SR₁, —CHR₂NR₁R2, —CHR₁NHR₂, —CHR₁,N(CH₃)R₂, or—NR₁₂NR₁R₂; Z is NH, O, S, —N (C₁-C₂ alkyl)-, —N(C(O)CF₃), - or—C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄ are each, independently, hydrogen,trifluoromethyl or methyl, or one of R₁₃ and R₁₄ is cyano and the otheris hydrogen or methyl, or —C(R₁₃R₁₄) is a cyclopropyl group, or Z isnitrogen or CH and forms a five or six membered heterocyclic ring fusedwith R₅, which ring optionally comprises two or three further heteromembers selected independently from oxygen, nitrogen, NR₁₂, andS(O)_(m), and optionally comprises from one to three double bonds, andis optionally substituted with halo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), NH₂,NHCH₃, N(CH₃)₂, CF₃, or OCF₃, with the proviso that said ring does notcontain any —S—S—, —S—O—, —N—S—, or —O—O— bonds, and does not comprisemore than two oxygen or S(O)_(m) heterologous members; R₁ is C(O)H,C(O)(C₁-C₆ hydrocarbyl), C(O)(C₁-C₆ hydrocarbylene)(C₃-C₈cyclohydrocarbyl), C(O)(C₃-C₈ cyclohydrocarbylene )(C₃-C₈cyclohydrocarbyl), C(O)(C₁-C₆ hydrocarbylene)(C₄-C₈heterocyclohydrocarbyl ), —C(O)(C₃-C₈ cyclohydrocarbylene)(C₄-C₈heterocyclohydrocarbyl), C₃-C₈ cyclohydrocarbyl, C₄-C₈heterocyclohydrocarbyl, —(C₁-C₆ hydrocarbylene (C₃-C₈ cyclohydrocarbyl),C₃-C₈ cyclohydrocarbylene)(C₃-C₈ cyclohydrocarbyl),—(C₁-C₆hydrocarbylene)(C₄-C₈ heterocyclohydrocarbyl), —(C₃-C₈cyclohydrocarbylene)(C₄-C₈ heterocyclohydrocarbyl), or —O-aryl, or—O—(C₁-C₆ hydrocarbylene)-aryl; wherein said aryl, C₄-C₈heterocyclohydrocarbyl, C₁-C₆ hydrocarbyl, C₃-C₈ cyclohydrocarbyl, C₃-C₈cyclohydrocarbylene, and C₁-C₆ hydrocarbylene groups may eachindependently be optionally substituted with from one to six fluoro andmay each independently be optionally substituted with one or twosubstituents R₈ independently selected from the group consisting ofC₁-C₄ hydrocarbyl, —C₃-C₈ 1 cyclohydrocarbyl, hydroxy, chloro, bromo,iodo, CF₃, —O—(C₁-C₆ hydrocarbyl), —O—(C₃-C₅ cyclohydrocarbyl),—O—CO—(C₁-C₄ hydrocarbyl), —O—CO—NH(C₁-C₄ hydrocarbyl),—O—CO—N(R₂₄)(R₂₅), —N(R₂₄)(R₂₅), —S(C₁-C₄ hydrocarbyl), —S(C₃-C₅cyclohydrocarbyl) [−]-N(C₁-C₄ hydrocarbyl)CO(C₁-C₄ hydrocarbyl),—NHCO(C₁-C₄ hydrocarbyl), —COO(C₁-C₄ hydrocarbyl), —CONH(C₁-C₄hydrocarbyl), —CONC₁-C₄ hydrocarbyl)(C₁-C₂ hydrocarbyl), CN, NO₂,—OSO₂(C₁-C₄ hydrocarbyl), S⁺(C₁-C₆ hydrocarbyl)(C₁-C₂ hydrocarbyl) I⁻,—SO(C₁-C ₄ hydrocarbyl) and —SO₂(C₁-C₄ hydrocarbyl); and wherein theC₁-C₆ hydrocarbyl, C₁-C₆ hydrocarbylene, C₅-C₈ cyclohydrocarbyl, C₅-C₈cyclohydrocarbylene, and C₅-C₈ heterocyclohydrocarbyl moieties of R₁ mayoptionally independently contain from one to three double or triplebonds; and wherein the C₁-C₄ hydrocarbyl moieties and C₁-C₆ hydrocarbylmoieties of R₈ can optionally independently be substituted with hydroxy,amino, C₁-C₄ alkyl, aryl, —CH₂-aryl, C₃-C₅ cycloalkyl, or —O—(C₁-C₄alkyl), and can optionally independently be substituted with firom oneto six fluoro, and can optionally contain one or two double or triplebonds; and wherein each heterocyclohydrocarbyl group of R₁ contains fromone to three heteromoieties selected from oxygen, S(O)_(m), nitrogen,and NR₁₂; R₂ is hydrogen, C₁-C₁₂ hydrocarbyl, C₃-C₈ cyclohydrocarbyl,C₄-C₈ heterocyclohydrocarbyl, —(C₁-C₆ hydrocarbylene)(C₃-C₈cyclohydrocarbyl), —(C₃-C₈ cyclohydrocarbylene)(C₃-C₈ cyclohydrocarbyl),—(C₁-C₆ hydrocarbylene)(C₄-C₈ heterocyclohydrocarbyl), —(C₃-C₆cyclohydrocarbylene)(C₄-C₈ heterocyclohydrocarbyl), aryl, —(C₁-C₆hydrocarbylene)aryl, or —(C₃-C₈ cyclohydrocarbylene)(aryl); wherein eachof the foregoing R₂ groups may optionally be substituted with from oneto three substituents independently selected from chloro, fluoro, andC₁-C₆ alkyl, wherein one of said one to three substituents can furtherbe selected from bromo, iodo, C₁-C₆ alkoxy, —OH, —O—CO—(C₁-C₆ alkyl),—O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S (C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl),—S(O)₂(C₁-C₆ alkyl), S⁺(C₁-C₆ alkyl)(C₁-C₂ alkyl)I′, CN, and NO₂; andwherein the C₁-C₁₂ hydrocarbyl, —(C₁-C₆ hydrocarbylene), andcyclohydrocarbyl gropups of 5-8 carbon atoms, cyclohydrocarbylene groupsof 5 to 8 carbon atoms and heterocyclohydrocarbyl groiups of 5 to 8atoms of R₂ may optionally independently contain from one to threedouble or triple bonds; and wherein each heterocyclohydrocarbyl group ofR₂ contains from one to three heteromoieties selected from oxygen,S(O)_(m), nitrogen, and NR₁₂; or when R₁ and R₂ are as in —NHCHR₁R₂,—OCHR₁R₂, —SCHR₁R₂, —CHR₁R₂ or —NR₁R₂, R₁ and R₂ of B may form asaturated 5- to 8-membered ring which may optionally contain one or twodouble bonds and in which one or two of the ring carbons may optionallybe replaced by an oxygen, S(O)_(m), nitrogen or NR₁₂; and whichcarbocyclic ring can optionally be substituted with from 1 to 3substituents selected from the group consisting of hydroxy, C₁-C₄ alkyl,fluoro, chloro, bromo, iodo, CF₃, —O—(C₁-C₄ alkyl), —O—CO—(C₁-C₄ alkyl),—O—CO—NH(C₁-C₄ alkyl), —O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —N(C₁-C₄alkyl)CO(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl),—COO(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), CN, NO₂, —OSO₂(C₁-C₄ alkyl),—SO(C₁-C₄ alkyl), and —SO(C₁-C₄ alkyl), wherein one of said one to threesubstituents can further be selected from phenyl; R₃ is methyl, ethyl,fluoro, chloro, bromo, iodo, cyano, methoxy, OCF₃, NH₂, NH(C₁-C₂ alkyl),N(CH₃)₂, —NHCOCF₃, —NHCH₂CF₃, S(O)_(m)(C₁-C₄ alkyl), CONH₂, —CONHCH₃,CON(CH₃)₂, —CF₃, or CH₂OCH₃; R₄ is hydrogen, C₁-C₄ hydrocarbyl, C₃-C₅cycloalkyl, —(C₁-C₄ hydrocarbylene)(C₃-C₅ cycloalkyl), —(C₃-C₅cycloalkylene)(C₃-C₆ cycloalkyl), cyano, fluoro, chloro, bromo, iodo,—OR₂₄ C₁-C₆ alkoxy, —O— cycloalkyl), —O—(C₁-C₄ hydrocarbylene)(C₃-C₅cycloalkyl), —O—(C₃-C₅ cycloalkylene)(C₃-C₅ cycloalkyl),—CH₂SC(S)O(C₁-C₄ alkyl), CH₂OCF₃, CF₃, amino, nitro, —NR₂₄R₂₅, —(C₁-C₄hydrocarbylene)-OR₂₄, —(C₁-C₄ hydrocarbylene)Cl, —(C₁-C₄hydrocarbylene)NR₂₄R₂₅, —NHCOR₂₄, —NHCONR₂₄R₂₅, —CH═NOR₂₄, —NHNR₂₄R₂₅,—S(O)_(m)R₂₄, —C(O)R₂₄, —OC(O)R₂₄, —C(O)CN, —C(O)NR₂₄R₂₅,—C(O)NHNR₂₄R₂₅, and —COOR₂₄, wherein the hydrocarbyl and hydrocarbylenegroups of R₄ may optionally independently contain one or two double ortriple bonds and may optionally independently be substituted with one ortwo substituents R₁₀ independently selected from hydroxy, amino,—NHCOCH₃, —NHCOCH₂Cl, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₂alkyl),—COO(C₁-C₄ alkyl), —COOH, —CO(C₁-C₄ alkyl), C₁-C₆ alkoxy, C₁-C₃thioalkyl, cyano and nitro, and with one to four substituentsindependently selected from fluoro and chloro; R₅ is aryl or heteroaryland is substituted with from one to four substituents R₂₇ independentlyselected from halo, C₁-C₁₀ hydrocarbyl, —(C₁-C₄ hydrocarbylene)(C₃-C₈cycloalkyl), —(C₁-C₄ hydrocarbylene)(C₄-C₈ heterocycloalkyl), —(C₃-C₈cycloalkyl), —(C₄-C₈ heterocycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈cycloalkyl), —(C₃-C₈ cycloalkylene)(C₄-C₈ heterocycloalkyl), C₁-C₄haloallyl, C₁-C₄ haloalkoxy, nitro, cyano, —NR₂₄R₂₅, —NR₂₄COR₂₅,—NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅, —CONR₂₄R₂₅, —CON(OR₂₂)R₂₃, —CO₂R₂₆,—C═N(OR₂₂)R₂₃, and —S(O) _(m)R₂₃; wherein said C₁-C₁₀ alkyl, C₃-C₈cycloalkyl, (C₁-C₄ hydrocarbylene), (C₃-C₈ cycloalkyl), (C₃-C₈cycloalkylene), and (C₄-C₈ heterocycloalkyl) groups can be optionallysubstituted with from one to three substituents independently selectedform C₁-C₄ alkyl, C₃-C₈ cycloalkyl, (C₁-C₄ hydrocarbylene)(C₃-C₈cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), C₁-C₄ haloalkyl,hydroxy, C₁-C₆ alkoxy, nitro, halo, cyano, —NR₂₄R₂₅, —NR₂₄COR₂₅,NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅, —CONR₂₄R₂₅, CO₂R₂₆, —CO(NOR₂₂)R₂₅, and—S(O)_(m)R₂₃; and wherein two adjacent substituents of the R₅ group canoptionally form a 5-7 membered ring, saturated or unsaturated, fused toR₅, which ring optionally can contain one, two, or three heterologousmembers independently selected from O, S(O)_(m), and N, but not any—S—S—, —O—O—, —S—O—, or —N—S— bonds, and which ring is optionallysubstituted with C₁-C₄ alkyl, C₃-C₈ cycloalkyl, —(C₁-C₄ alkylene)(C₃-C₈cycloalkyl), —(C₃-C₈ cyloalkylene)(C₃-C₈ cycloalkyl), C₁-C₄ haloalkyl,nitro, halo, cyano —NR₂₄R₂₅, NR₂₄COR₂₅, NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅,—CONR₂₄R₂₅, CO₂R₂₆, —CO(NOR₂₆)R₂₅, or —S(O)_(m)R₂₃; wherein one of saidone to four optional substituents R₂₇, can further be selected from—SO₂NH(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkylene )(C₃-C₈ cycloalkyl),SO₂NH(C₃-C₈ cycloalkyl), —SO₂NH(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),—SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl),—NHSO₂(C₃-C₈ cycloalkyl), —NHSO₂(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), and—NHSO₂(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl); and wherein thehydrocarbyl, and hydrocarbylene groups of R₅ may independentlyoptionally contain one double or triple bond; R₆ is hydrogen, C₁-C₆alkyl, C₃-C₈ cycloalkyl, —(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), or —(C₃-C₈cycloalkylene)(C₃-C₈ cycloalkyl), wherein said alkyl and cycloalkyl mayoptionally be substituted with one hydroxy, methoxy, ethoxy or fluorogroup; or R₆ and R₄ can together form an oxo (═O) group, or can beconnected to form a 3-8 membered carbocyclic ring, optionally containingone to three double bonds, and optionally containing one, two, or threeheterologous ring members selected from O, SO_(m), N, and NR₁₂, but notcontaining any —O—O—, —S—O—, —S—S—, or —N—S— bonds, and furtheroptionally substituted with C₁- C₄ hydrocarbyl or C₃-C₆ cycloalkyl,wherein said C₁-C₄ hydrocarbyl substituent may optionally contain onedouble or triple bond; R₇ is hydrogen, methyl, fluoro, chloro, bromo,iodo, cyano, hydroxy, —O(C₁-C₂) alkyl), —O(cyclopropyl), —COO(C₁-C₂alkyl), —COO(C₃-C₈ cycloalkyl), —OCF₃, —CF₃, —CH₂OH or CH₂OCH₃; R₁₁ ishydrogen, hydroxy, fluoro, ethoxy, or methoxy; R₁₂ is hydrogen or C₁-C₄alkyl; R₂₂ is independently at each occurrence selected from hydrogen,C₁-C₁₄ alkyl, C₁-C₁₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₈cycloalkyl, (C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), and (C₁-C₄)alkylene)(C₃-C₈ cycloalkyl); R₂₃ is independently at each occurrenceselected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₈cycloalkyl, —(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈cycloalkylene)(C₃-C₈ cycloalkyl), aryl, —(C₁-C₄ alkylene)aryl,piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, andthiomorpholine; R₂₄ and R₂, are independently at each occurrenceselected from hydrogen, —C₁-C₄ alkyl, C₁-C₄ haloalkyl, —(C₁-C₄alkylene)OH, —(C₁-C₄ alkylene)—O—(C₁-C₄ alkyl), —(C₁-C₄alkylene)—O—(C₃-C₅ cycloalkyl), C₃-C₈ cycloalkyl, —(C₁-C₄alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),—C₄-C₈ heterocyclohydrocarbyl, —(C₁-C₄ alkylene)(C₄-C₈heterocyclohydrocarbyll), —(C₃-C₈ cycloalkylene)(C₄-C₈heterocyclohydrocarbyl), aryl, and —(C₁-C₄ alkylene)(aryl), wherein the—C₄-C₈ heterocyclohydrocarbyl groups can each independently optionallybe substituted with aryl, CH₂-aryl, or C₁-C₄ alkyl, and can optionallycontain one or two double or triple bonds; or, when R₂₄ and R₂₅ are asNR₂₄R₂₅, —C(O)NR₂₄R₂₅, —(C₁-C₄alkylene)NR₂₄R₂₅, or —NHCONR₂₄R₂₅, thenNR₂₄R₂₅ may further optionally form a 4 to 8 membered heterocyclic ringoptionally containing one or two further hetero members independentlyselected from S(O)_(m), oxygen, nitrogen, and NR₁₂, and optionallycontaining from one to three double bonds; R₂₆ is independently at eachoccurrence selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₈ cycloalkyl,—(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈cycloalkyl), aryl, and —(C₁-C₄ alkylene)(aryl); and wherein each m isindependently zero, one, or two, with the proviso thatheterocyclohydrocarbylene groups of the compound of formula I, do notcomprise any —S—S—, —S—O—, —N—S—, or —O—O— bonds, and do not comprisemore than two oxygen or S(O)_(m) heterologous members.
 30. Apharmaceutical composition according to claim 29 for the treatment of adisorder selected from inflammatory disorders; pain, asthma, psoriasisand allergies; generalized anxiety disorder; panic; phobias; obsessivecompulsive disorder; post-traumatic stress disorder; sleep disordersinduced by stress; pain perception; mood disorders; dysthemia; bipolardisorders; cyclothymia; fatigue syndrome; stress induced headache;cancer; irritable bowel syndrome, Crohn's disease; spastic colon; humanimmunodeficiency virus (HIV) infections; neurodegenerative diseases;gastrointestinal diseases; eating disorders; chemical dependencies andaddictions; obesity; infertility; head traumas; spinal cord trauma;ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke;immune dysfunctions; muscular spasms; urinary incontinence; seniledementia of the Alzheimer's type; multi infarct dementia; amyotrophiclateral sclerosis; and hypoglycemia in a mammal.
 31. A pharmaceuticalcomposition as claimed in claim 29 for treatment of a mood disorderselected from the group consisting of rheumatoid arthritis andosteoarthritis, pain, asthma, psoriasis and allergies.
 32. Apharmaceutical composition as claimed in claim 29 for treatment of aninflammatory disorder selected from the group consisting of rheumatoidarthritis and osteoarthritis.
 33. A pharmaceutical composition asclaimed in claim 30 for treatment of depression, selected from the groupconsisting of major depression, single episode depression, recurrentdepression, and child abuse induced depression.
 34. A pharmaceuticalcomposition as claimed in claim 30 for treatment of neurodegenerativediseases selected from the group consisting of Alzheimer's disease,Parkinson's disease and Huntington's disease.
 35. A pharmaceuticalcomposition as claimed in claim 30 for treatment of chemicaldependencies or addictions, selected from the group consisting ofdependencies or addictions to alcohol, cocaine, heroin, benzodiazapines,or other drugs.
 36. A pharmaceutical composition as claimed in claim 30for treatment of cerebral ischemia.
 37. A pharmaceutical composition asclaimed in claim 30 for treatment of stress induced immune dysfunctionsselected from the group consisting of porcine stress syndrome, bovineshipping fever, equine paroxysmal fibrillation, confinement dysfunctionin chicken, sheering stress in sheep, and human animal interactionstress in dogs.
 38. A pharmaceutical composition as claimed in claim 30for treatment of fibromyalgia.
 39. A pharmaceutical composition asclaimed in claim 30 for treatment of anorexia or bulimia nervosa.
 40. Apharmaceutical composition as claimed in claim 30 for treatment ofcerebral ischemia selected from cerebral hippocampal ischemia.
 41. Apharmaceutical composition as claimed in claim 30 for treatment ofincluding social phobia, agoraphobia or specific phobias.
 42. Thepharmaceutical composition according to claim 29 wherein the painperception is fibromyalgia.
 43. The pharmaceutical composition accordingto claim 29 wherein the ischemic neuronal damage is cerebral ischemia.44. The pharmaceutical composition according to claim 30 wherein mooddisorder is depression or postpartum depression.
 45. The pharmaceuticalcomposition according to claim 30 wherein the ischemic neuronal damageis cerebral ischemia.
 46. The pharmaceutical composition according toclaim 30 wherein the mammal is a human.